Fragment events in 2025 and 2026

For better or for worse, 2025 is half-way over. There are still some good conferences coming up, and 2026 is also starting to take shape.

September 21-24: FBLD 2025 will be held in the original Cambridge (UK),  where it was supposed to be held in 2020. This will mark the ninth in an illustrious series of conferences organized by scientists for scientists. You can read impressions of FBLD 2024, FBLD 2018, FBLD 2016, FBLD 2014, FBLD 2012, FBLD 2010, and FBLD 2009. 

 

September 22-25: You'll need to make a tough choice: FBLD 2025 or CHI’s Twenty-Third Annual Discovery on Target in Boston. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2024 meeting, the 2023 meeting, the 2022 meeting, the 2021 meeting, the 2020 virtual meeting, the 2019 meeting, and the 2018 meeting.

 

November 11-13: CHI holds its second Drug Discovery Chemistry Europe in beautiful Barcelona. This will include tracks on lead generation, protein-protein interactions, degraders and glues, and machine learning, with multiple fragment talks throughout. 

2026

February 17-19:  The Twelfth NovAliX Conference will be held for the first time in San Diego! (Please note the date and location change.) You can read my impressions of the 2018 Boston event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event here, here, and here. 

 

April 13-16: CHI’s Fragment-Based Drug Discovery turns 21, old enough to legally drink in the US! The longest-running annual fragment event returns as always to San Diego. This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2025 meeting, the 2024 meeting, the 2023 meeting, the 2022 meeting, the 2021 virtual meeting, the 2020 virtual meeting, the 2019 meeting, the 2018 meeting, the 2017 meeting, the 2016 meeting; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting; the 2011 meeting; and the 2010 meeting. 

September 14-16: RSC-BMCS Tenth Fragment-based Drug Discovery Meeting will be held in Cambridge, UK.  You can read my impressions of the 2024 meeting, the 2013 meeting, and the 2009 meeting.

 

Know of anything else? Please leave a comment or drop me a note.

Fragment events in 2025

After a bumper year for conferences in 2024, this year is also shaping up to be eventful. 

April 14-17: CHI’s Twentieth Annual Fragment-Based Drug Discovery, the longest-running annual fragment event, returns as always to San Diego. This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2024 meeting here, the 2023 meeting here, the 2022 event here, the 2021 virtual meeting here, the 2020 virtual meeting here, the 2019 meeting here, the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here. 

 

May 5-6: Returning after a five year hiatus, Industrial Biostructures of America will be held in Cambridge, MA and includes a session on FBLD. 

June 2-4:  The Eleventh NovAliX Conference returns to the stunning city of Strasbourg. You can read my impressions of the 2018 Boston event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event here, here, and here.

September 21-24: FBLD 2025 will be held in the original Cambridge (UK),  where it was supposed to be held in 2020. This will mark the ninth in an illustrious series of conferences organized by scientists for scientists. You can read impressions of FBLD 2024, FBLD 2018, FBLD 2016, FBLD 2014, FBLD 2012, FBLD 2010, and FBLD 2009. 

 

September 22-25: You'll need to make a tough choice: FBLD 2025 or CHI’s Twenty-Third Annual Discovery on Target. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2024 meeting here, the 2023 meeting here, the 2022 meeting here, the 2021 event here, the 2020 virtual event here, the 2019 event here, and the 2018 event here.

 

Finally, from November 11-13 CHI holds its second Drug Discovery Chemistry Europe in beautiful Barcelona. This will include likely tracks on lead generation, protein-protein interactions, degraders, machine learning, and probably several fragment talks. 

   

Know of anything else? Please leave a comment or drop me a note.

FBLD 2024

The FBLD meetings have always been calendar highlights. Starting in 2008, before Practical Fragments even existed, they have graced cities around the world in 2009, 2010, 2012, 2014, 2016, and 2018. The plan was for 2020 to be held in Cambridge, UK, but for obvious reasons that didn’t happen. Last week, Boston hosted a triumphant return of the event. With more than 30 talks and dozens of posters I’ll just touch on a few major themes.

 

Crystallography

High-throughput crystallography was prevalent, as befits its growing role in fragment finding. (If you haven’t yet voted in our methods poll on the right side of the page please do so!) Debanu Das (XPose Therapeutics) described how crystallographic screens of just a few hundred fragments identified hits against DNA-damage response proteins such as APE1; these have been advanced to high-nanomolar inhibitors with cell activity. And Andreas Pica described the ALPX platform that enabled screening >4000 hits from an HTS screen against PDEδ resulting in >500 structures.

 

The Diamond Light Source was a pioneer in developing high-throughput crystallography methods, and several speakers described continued progress. Blake Balcomb noted that since 2015 they have collected >240,000 datasets and identified >30,000 ligands. Of these, some 3750 have been deposited into the Protein Data Bank.

 

A crystallographic fragment hit is just the start, and Frank von Delft emphasized that “fragment progression is neither fast nor cheap.” His goal is to take a 100 µM binder to a 10 nM lead in less than a week for less than £1000. Toward this end he and his team are using rapid chemical synthesis and crude reaction screening along with various computational approaches and crowd-sourced science. The COVID Moonshot, which we wrote about here, is one model, and Diamond is trying to create a “Moonshot factory” to pursue other viral targets.

 

Computational Approaches

Computational methods are potentially the least expensive fragment-to-lead method, and these were well represented. One challenge is screening the massive chemical space represented by make-on-demand libraries, and Pat Walters (Relay) described how this can be done using Thompson Sampling, an active-learning method that traces its origins to 1933. Applied to lead discovery, the method involves breaking larger molecules into component fragments and iteratively searching for better binders. Pat showed that searching just 0.1% of a library of 335 million molecules consistently found 90% of the best hits.

 

Most computational methods rely on experimental data, and over the past 25 years Astex has generated >100 crystal structures on each of more than 40 targets, with >6600 bound fragments in total. Paul Mortenson described how these are being used to develop generative models, with chemists providing feedback on suggested molecules.

 

Artificial intelligence is the centerpiece of Isomorphic Labs, which has unfettered access to AlphaFold 3. Rebecca Paul described an example starting from a literature fragment in which the predicted affinities matched well with experiment – and the molecules were considerably more potent than those suggested by an experienced medicinal chemist.

 

Recognizing the need for experimental affinity data for fragments, Isomorphic worked with Arctoris to screen 5420 fragments against 65 kinases covering the diversity of the kinome. After carefully curating the data, including rescreening the actives at a different CRO, they found 485 fragments with an IC₅₀ of 300 µM or better. Interestingly, only about half of these fragments are known kinase binders.

 

Sandor Vajda (Boston University) suggested there may be limitations to machine learning models. He found that using AlphaFold 2 to find cryptic pockets was dependent on their representation in the PDB, with rare experimental states not being predicted. Sandor also proposed an interesting hypothesis that cryptic pockets created only by the movement of side chains are not very ligandable because the side chains move on such a rapid time scale that they effectively act as competitive inhibitors to ligands.

 

Success Stories

No FBLD meeting would be complete without success stories, and FBLD 2024 was no exception. Chaohong Sun noted that nearly 80% of the targets at AbbVie taken into fragment-based screening are novel. Of these, more than 80% yield actionable hits, though 44% are not pursued for a variety of reasons, including finding hits from other sources, hits at novel sites with no obvious function, and changes to the portfolio. Chaohong described a series of STING agonists that was taken forward to low nanomolar leads with in vivo activity.

 

Michelle Arkin (UCSF) described progress on creating molecular glues to link 14-3-3 proteins to the estrogen receptor, which we last wrote about here. Covalent binders to the 14-3-3 protein stabilize the interaction with ERα by more than 100-fold and show activity in cancer cell models.

 

Multiple talks focused on SARS-CoV-2 targets. Ashley Taylor (Vanderbilt) described fragment screens against the papain-like protease PL^Pro that led to both covalent and non-covalent inhibitors. James Fraser (UCSF) described how a massive crystallographic screen against the Nsp3 macrodomain Mac1 led to high nanomolar compounds, which we wrote about here. And Adam Renslo (UCSF) discussed the further optimization of Mac1 inhibitors to yield molecules that could protect mice from a fatal challenge of the virus.

 

A drawback of pursuing novel targets is that sometimes the biology proves uncooperative. Andrew Woodhead described a successful fragment screen at Astex against the oncology target elF4E that led to mid-nanomolar binders that could disrupt the protein-protein interaction with eIF4G in cells. Surprisingly, these molecules had no effect on cell viability, and a series of mutational and targeted-protein degradation experiments suggested that blocking a larger region of the protein-protein binding site might be necessary.

 

Drugs are the ultimate success stories, as David Rees reminded participants in “25 years of thinking small.” In addition to providing an overview of FBLD at Astex, David added up the sales of all seven FDA-approved fragment-derived drugs, which totals more than $3 billion. Harder to quantify—though infinitely more valuable—are the added years of life for patients with once-untreatable cancers. These numbers will only grow as the dozens of fragment-derived molecules in the clinic continue to advance.

 

I’ll close on that note. If you missed FBLD 2024, you’ll have another chance next year: FBLD 2025 is planned for Cambridge (UK) September 21-24 next year. Barring global pandemics.

Fragment-based Drug Discovery Down Under (FBDD-DU) 2024

The end of June brought me to Brisbane for the fifth FBDD-DU Conference, which was meeting for the first time outside Melbourne. This was also my first FBDD-DU conference since 2019, and it was nice to see a wide range of talks from around Australia and beyond. As always, I won’t attempt to be comprehensive, so if you attended, please feel free to add your observations.

 

Techniques

Experimental techniques received considerable attention. Félix Torres (NexMR) described using an inexpensive benchtop NMR that doesn’t require liquid helium. Fragments were screened using photochemically induced dynamic nuclear hyperpolarization (photo-CIDNP). The method is so rapid that it is limited more by sample handling than data collection, and the Torres team is speeding things up using flow technology. Right now photo-CIDNP is still very much DIY, but rumor has it that Bruker may soon launch a photochemical module for their benchtop instrument.

 

We’ve written about high-throughput crystallographic screening at the Diamond Light Source, and synchrotrons around the world are building similar platforms. Kate Smith described integrated systems at the Swiss Light Source which automate crystallization, fragment screening, data collection, and data processing. She also described increasing automation of fragment screening using the free-electron laser (FEL), which we wrote about here. Current throughput is around 40 compounds per day and requires large amounts of protein, but these are still early days.

 

Australia is building their own high-throughput crystallography platform, and various components were described by Roxanne Smith (University of Melbourne), Gautham Balaji (Monash Univesrity), and Yogesh Khandokar (ANSTO-Australian Synchrotron). Watch this space!

 

Speaking of Australia, Nyssa Drinkwater described Compounds Australia, a national repository of more than 2.5 million molecules, including several fragment collections. Members, who can be from outside Australia, can store their own libraries within the facility to ease collaborations with other groups, and they can also access public libraries of compounds, including unusual Antipodean natural product extracts. I was fortunate to be able to visit the facility at Griffith University and can attest that it is easily the equal of those in large pharma.

 

Turning to mass spectrometry, Sally-Ann Poulsen (Griffith University) described covalent library screening against PRMT5, a target we’ve written about here. Sally-Ann is also a pioneer of (conventionally non-covalent) native mass spectrometry, and she described applying this methodology to screen small molecules against RNA.

 

But the star of the conference was SPR, appearing in multiple talks. Long-time readers may recall an instrument made by SensiQ, with its gradient injection capability to accelerate data collection. This is now marketed by Sartorius, and Lauren Hartley-Tassell (Griffith University) described using it to screen a glycoprotein. The larger plumbing in the instrument is less prone to clogging, and Lauren said it can even accommodate screening of whole cells.

 

Anything to accelerate the (sometimes painful) process of advancing fragments is always welcome. As Jason Pun (Monash University) noted, eight of nine targets screened in Martin Scanlon’s group started with fragments having affinities worse than 100 µM. Off-rate screening, an SPR technique we wrote about here, can rapidly identify more potent molecules from crude reaction mixtures, but data processing can be tedious. Jason described new software tools to automate this process, and hopefully he will publish the methodology and code. (An aside: over coffee Yun Shi of Griffith University noted that off-rate screening, or ORS, should really be called off-rate constant screening, which would give the more amusing acronym ORCS.)

 

Targets

Turning to targets, Ben Davis (Vernalis) described a collaboration with Servier to advance oncology target USP7 inhibitors from a literature fragment to a preclinical candidate. Crude reaction mixture screening was used extensively, not just by SPR but even in microsome stability studies. Unfortunately the project ended when on-target toxicology effects emerged, which were perversely more severe in higher animal species than they were in mice.

 

Yun Shi described finding tiny heterocyclic fragments that react with the NAD⁺ cofactor of neurodegenerative target SARM1 in situ to generate a potent inhibitor, as we wrote about here. Yun is using ¹⁹F NMR to follow the base-exchange reaction to identify inhibitors to other glycohydrolases too.

 

Deaths due to E. coli are – somewhat surprisingly – more common than those caused by any other pathogen, and Christina Spry described her work at the National Australian University to discover inhibitors of the essential dephosphocoenzyme A kinase (GPCK) enzyme, which catalyzes the final step in the synthesis of Coenzyme A (CoA). Fragment screening by DSF and NMR identified a weak (K_D=380 µM) binder, and fragment growing has led to a low nanomolar inhibitor that is selective against the human form of the enzyme.

 

Continuing the E. coli theme, several talks discussed efforts against the challenging bacterial virulence target DsbA, a twenty-year campaign in Martin Scanlon’s group at Monash as noted by Yildiz Tasdan. The enzyme has a shallow, hydrophobic active site, but the discovery of fragments binding to a cryptic site and crude-reaction screening by ORS (ORCS?) and affinity-selected mass spectrometry (ASMS) has finally led to molecules with dissociation constants around 1 µM.

 

Finally, in his closing keynote address Alvin Hung, who recently founded NeuroVanda, described a wide range of fragment success stories, many of them covered on Practical Fragments, against targets including pantothenate synthetase, GSK3β, PKC-ι, and MNK1/2. Although structural enablement helped in many cases, Alvin was not rigid about the need for atomic-level details: in response to the question whether he would advance a fragment in the absence of structure, he answered simply, “of course.” Perhaps it's time to redo my poll on this subject.

 

I’ll wrap up here, but if you missed this or earlier events this year there are still a couple more conferences in Boston, and 2025 is already starting to take shape.

Fragment events in 2024

We don't know for sure what 2024 has in store for us, but barring pandemics or other disasters, the year is shaping up to be an annus mirabilis for fragments. For the first time ever, all four of the recurring fragment meetings are scheduled for the same year, and other conferences also look exciting. I hope to see you at one.

March 3-5: RSC-BMCS Ninth Fragment-based Drug Discovery Meeting will be held in Cambridge, UK. This venerable biannual event will be particularly focused on case studies "that have delivered compounds to late stage medicinal chemistry, preclinical, or clinical programmes." You can read my impressions of the 2013 meeting here and the 2009 event here.

 

April 1-4: CHI’s Nineteenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, returns as always to San Diego. This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2023 meeting here, the 2022 event here, the 2021 virtual meeting here, the 2020 virtual meeting here, the 2019 meeting here, the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here. 

 

June 2-4:  The theme of the Tenth NovAliX Conference, to be held in the Swiss resort town of Brunnen, is "reinventing drug discovery." You can read my impressions of the 2018 Boston event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event here, here, and here.

 

June 25-27: FBDD Down Under 2024 will take place in beautiful Brisbane. I believe this is the fifth FBDD DU event and the first to be held outside Melbourne. You can read my impressions of FBDD DU 2019 and FBDD DU 2012.
 
September 22-25: After a six year hiatus, FBLD 2024 will be held in Boston. This will mark the eighth in an illustrious series of conferences organized by scientists for scientists. You can read impressions of FBLD 2018, FBLD 2016, FBLD 2014, FBLD 2012, FBLD 2010, and FBLD 2009.

 

September 30 to Oct 3: Autumn is usually a nice time of year in Boston, so why not stick around to attend CHI’s Twenty-Second Annual Discovery on Target. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2023 meeting here, the 2022 meeting here, the 2021 event here, the 2020 virtual event here, the 2019 event here, and the 2018 event here.

 

Know of anything else? Please leave a comment or drop me a note.

Discovery on Target 2023

Last week CHI’s Discovery on Target was held in Boston. This was the Twentieth Anniversary edition, though oddly last year also claimed to be the twentieth. Regardless, attendance surpassed pre-pandemic levels, with some 1200 attendees, 90% of them in person. Eight or nine concurrent tracks over the course of three days competed with one another, while a couple pre-conference symposia and a handful of short courses were held before the main event. Outside obligations kept me from seeing many talks, including plenary keynotes by Jay Bradner (Novartis), Anne Carpenter, and Shantanu Singh (both at the Broad Institute), but most of these were recorded and will be made available for a year, and I look forward to watching them. Here I’ll just touch on a few of the fragment-relevant talks I was able to attend.

 

“Protein Degraders and Molecular Glues” was a popular track during all three days of the main conference, and in a featured presentation Steve Fesik (Vanderbilt) described how he is using NMR-based FBLD to identify tissue-specific E3 ligases and β-catenin degraders. In the case of β-catenin, a difficult oncology target, a fragment screen identified a 500 µM hit that was optimized to 10-20 nM. This has no functional activity on its own, but combining it with a ligand for an E3 ligase to generate a bivalent PROTAC causes degradation of the protein. Steve is currently optimizing the pharmaceutical properties of these molecules.

 

One exciting application for PROTACs is tissue-specific targeted protein degradation, which could avoid systemic toxicity for proteins such as Bcl-x_L. Steve said that for the past five years he has been pursuing ligands against E3 ligases preferentially expressed in certain tissues, and he presented brief vignettes for three of them. These came from an initial list of 20 E3 targets, but many of them turned out to be too difficult to express.

 

Steve typically screens a library of nearly 14,000 fragments, large according to our recent poll, but this has proven fruitful as only about 10% of proteins he has screened have turned out to be “teflon.” He noted the odd little fragment hit that proved so impactful to the KRAS program we highlighted last year as being something that might have been excluded from a smaller library.

 

We wrote last week about ligands for the E3 ligase DCAF1, and Rima Al-Awar (Ontario Institute for Cancer Research) described another series. She also described ligands against the oncology target WDR5, a target Steve Fesik has pursued as well.

 

Continuing the theme of targeted protein degradation, Jing Liu described Cullgen’s discovery of fragment-sized ligands for a broadly-expressed E3 ligase which could be an alternative to CRBN-targeting ligands when resistance (inevitably) arises. Although he did not specify the E3 ligase, Cullgen has filed a patent application for ligands targeting DCAF1.

 

Rounding out targeted protein degradation, Kevin Webster, my colleague at Frontier Medicines, described the discovery of covalent ligands for the E3 ligase DCAF2 (or DTL) using chemoproteomics and a variety of other techniques including cryo-electron microscopy. Consistent with Steve’s comments, considerable effort went into successfully obtaining a soluble, well-behaved protein.

 

The late Nobel laureate Sydney Brenner said that “progress in science depends on new techniques, new discoveries, and new ideas, probably in that order.” Harvard’s Steve Gygi, one of Frontier’s Scientific Advisory Board members, described multiple new techniques in a featured presentation focused on cysteine-based profiling. These included multiplexed methods to more rapidly find covalent ligands for targets across the proteome. A just-released mass spectrometry instrument made by Thermo Fisher called the Astral further accelerates the process with order-of-magnitude improvements in both speed and sensitivity compared to existing machines.

 

The cell-based covalent screening described by Steve Gygi is very powerful, but so is investigating a single protein, as demonstrated by the discovery of sotorasib. AstraZeneca did early work on covalent screening (which Teddy noted in 2015), and they have continued to build their platform, as described by Simon Lucas. The company has around 12,000 covalent fragments, some beyond the rule of three, with molecular weights between 200 and 400 Da and logP between 0 and 4. More than 90% are acrylamides, a clinically validated warhead, and the researchers are careful to avoid particularly reactive molecules that would be non-specific.

 

In contrast to the electrophilic fragments that comprise most covalent libraries, Megan Matthews (University of Pennsylvania) is exploring nucleophilic fragments for “reverse polarity activity-based protein profiling,” as we highlighted last year. This has led to the discovery of unusual post-translational modifications. For example, the sequence of the protein SCRN3 suggests that it should be a cysteine hydrolase, but the purified protein has no cysteine hydrolase activity, and in cells the N-terminal cysteine is processed to form a glyoxylyl moiety.

 

Finally, Alex Shaginian provided an overview of DNA-encoded library screening (DEL) at HitGen. The company currently has 1.2 trillion compounds spread across more than 1500 libraries, and an obvious question is whether this is overkill. Alex noted that one protein has been screened three times over the course of several years. In the original screen, a modest (30 µM) hit was found from 4.2 billion compounds screened. A later screen of 130 billion compounds produced nothing new, but a more recent screen of 1 trillion compounds led to four mid-nanomolar series. As Steve Fesik noted, screening larger libraries, whether experimentally or computationally, really can be helpful, especially for the hardest targets.

 

Despite only attending half the conference this post is getting long, but for those of you who were there, which talks would you recommend watching?

Fragment events in 2023

Happy New Year!

Several good conferences are scheduled for this year, and while the organizers are hoping for robust in-person attendance there will still be virtual options. Hope to see you at one.

April 11-12: CHI’s Eighteenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, is set for sunny San Diego. This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2022 event here, the 2021 virtual meeting here, the 2020 virtual meeting here, the 2019 meeting here, the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here. 

 

April 26-28:  While not exclusively fragment-focused, the Ninth NovAliX Conference on Biophysics in Drug Discovery will have several relevant talks. For the first time in five years the event returns to the US (Philadelphia) and and will also offer virtual participation. You can read my impressions of the 2018 Boston event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event here, here, and here.

September 25-28: CHI’s Twenty-first Annual Discovery on Target will be held in Boston, as it was last year. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2021 event here, the 2020 virtual event here, the 2019 event here, and the 2018 event here.

 

Know of anything else? Please leave a comment or drop me a note.

Twentieth Annual Discovery on Target Meeting

Cambridge Healthtech Institute held its annual Discovery on Target meeting in Boston last week. Although it was technically a hybrid event, about 90% of attendees were physically present, so it really felt like a return to normalcy. Still, the online option was useful: just as with the spring DDC meeting, at least one speaker tested positive for COVID-19 and had to give his presentation remote. Also, with up to eight concurrent tracks, the fact that sessions were recorded for future viewing reduces FOMO, though likely at a cost of spontaneity (see our poll). Panel discussions were in-person only and not recorded, allowing for more candid conversations.

 

Fragments made appearances throughout the event. In a keynote talk, Steve Fesik (Vanderbilt) described work on several targets, most notably KRAS. Long-time readers will recall how NMR screens a decade ago identified molecules that bind to what has become known as the switch I/II pocket. Heroic efforts in collaboration with Boehringer Ingelheim have led to a chemical probe, but the biology around this particular site is complicated.

 

Also, the switch I/II pocket seems to be a magnet for fragments: all 25 crystallographically-characterized fragments from an NMR screen bound here. To look for new sites, the researchers introduced a cysteine residue to covalently block the switch I/II pocket with a known fragment, and then ran an NMR screen to find noncovalent binders at other sites. This identified fragments binding at the switch II pocket used by sotorasib. Extensive optimization and addition of a covalent warhead to target the G12C mutation led to clinical-stage BI 1823911. Steve emphasized the importance of diverse vectors for fragment growing and linking, and not being seduced by potency alone.

 

According to Christopher Davies of Genentech, one of the reasons KRAS has been so hard to drug is that it is very dynamic; in particular, the switch I and switch II loops can adopt multiple conformations. To constrain the protein, the researchers generated antibodies against the G12C mutant covalently bound to a small molecule inhibitor. One of these CLAMPs (Conformational Locking Antibody for Molecular Probe discovery) could stabilize the “open” form of the switch II pocket, thereby improving the affinity of ligands for this pocket and increasing the hit rate from an SPR-based fragment screen. (This work was published in Nat. Biotech. earlier this year.)

 

KRAS is a small GTPase. Samy Meroueh (Indiana University) discussed screening electrophilic fragments against Rgl2, which activates RAL, another small GTPase. We recently wrote about some of this work, and he mentioned that future publications are on the way.

 

Continuing the theme of difficult targets, Brad Shotwell described various hit-finding approaches used at AbbVie against the “cytokinome,” including IL-36γ, TNFα, and two sites on IL-17. We covered some of their TNFα work last year, and the IL-17 work will be the subject of a future post. In line with observations on other proteins, fragment hit rates predicted target ligandability.

 

The protein-protein interaction between NRF2 and KEAP1 is also a challenging target, and David Norton (Astex) discussed how a fragment-inspired virtual screen of the GlaxoSmithKline library ultimately led to low nanomolar inhibitors distinct from an earlier series. He emphasized the importance of growing fragments deliberately rather than attempting dramatic changes.

 

The pocket on KEAP1 is difficult because it is highly polar, but Marianne Schimpl (AstraZeneca) faced the opposite problem with the lipophilic allosteric site on MAT2a (work we highlighted last year). She mentioned the role of synthetic tractability: one fragment hit with higher LLE and Fsp³ was deprioritized in favor of a less shapely molecule that was more readily derivatized.

 

I spent much of the conference in PROTACs and molecular glues talks. Despite my arguments in 2018, FBLD is still not prominent here, but hopefully this will change. For PROTACs especially, which consist of two separate binding elements and a linker, minimizing the overall size is important. Indeed, Yue Xiong (Cullgen) described finding E3 ligands with molecular weights less than 300 Da. Despite only having micromolar affinity, they could be used to make highly effective PROTACs.

 

A broad view of drug discovery was provided by plenary keynote speaker Anabella Villalobos, who described the multiple therapeutic modalities used at Biogen to tackle neuroscience diseases. She mentioned that there are around 15 FDA-approved oligonucleotide-based drugs, but that this did not happen overnight: the first was approved more than a quarter century ago. This long “induction period” reminds me of my post last year comparing the rise of therapeutic antibodies with FBDD.

 

There is plenty more of interest; for those of you who attended, what talks would you recommend watching? And mark your calendars for September 25-28 next year, when DoT returns to Boston!

Fragment events in 2022 and 2023

The first third of 2022 has already been graced with two major fragment conferences. Two more have recently been added, and 2023 is starting to take shape.

May 9-11:  While not exclusively fragment-focused, the Eighth NovAliX Conference on Biophysics in Drug Discovery will have several relevant talks, and for the first time will use a hybrid model, both online and in Munich. You can read my impressions of the 2018 Boston event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event here, here, and here.

 

May 24-25:  BioSolveIT is holding a DrugSpace Symposium, with a heavy emphasis on fragments. It's both virtual and free, with an impressive lineup of speakers.

September 28-30: FBDD Down Under 2022 will take place in beautiful Melbourne. If you've been longing to travel, Australia has recently opened its borders. This is the fourth major FBDD event in the country, and given the success of the first and third, it should be excellent.

 

October 17-20: CHI’s Twentieth Annual Discovery on Target will be held both virtually and in Boston, as it was last year. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2020 virtual event here, the 2019 event here, and the 2018 event here.

 

 

2023

April 10-13: CHI’s Eighteenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, has already been scheduled for 2023 in San Diego. This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2022 event here, the 2021 virtual meeting here, the 2020 virtual meeting here, the 2019 meeting here, the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here. 

 
September: FBLD 2020 was sadly canceled due to COVID-19, but FBLD 2023 is scheduled to be held in Boston (exact dates TBD). This will mark the eighth in an illustrious series of conferences organized by scientists for scientists. You can read impressions of FBLD 2018, FBLD 2016, FBLD 2014,  FBLD 2012, FBLD 2010, and FBLD 2009.

 

Know of anything else? Please leave a comment or drop me a note!

Fragment events in 2022

Will 2022 mark the full return of in-person conferences? That's the plan - here's hoping SARS-CoV-2 doesn't interfere.

February 5-9: The  SLAS2022 International Conference and Exhibition will be held in Boston, so if you're looking for new instrumentation this is the place to be.

March 20-24: The American Chemical Society will hold its Spring National Meeting both in-person and virtually in San Diego. There are bound to be fragment talks, including a session on Modern Screening Methods on March 24.

March 27-29: The Royal Society of Chemistry's Fragments 2022 will be held in the original Cambridge, and also virtually. This is the eighth in an esteemed conference series that historically has alternated years with the FBLD meetings. You can read my impressions of Fragments 2013 and Fragments 2009.

 

April 19-20: CHI’s Seventeenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, returns in-person to sunny San Diego (and will also be online). This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2021 virtual meeting here, the 2020 virtual meeting here, the 2019 meeting here, the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here. 

May 9-11:  While not exclusively fragment-focused, the Eighth NovAliX Conference on Biophysics in Drug Discovery will have several relevant talks, and for the first time will use a hybrid model, both online and in Munich, Germany. You can read my impressions of the 2018 Boston event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event here, here, and here.

 

October 17-20: CHI’s Twentieth Annual Discovery on Target will be held both virtually and in Boston, as it was last year. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2020 virtual event here, the 2019 event here, and the 2018 event here.

 

Know of anything else? Please leave a comment or drop me a note!

Pacifichem 2021

Pacifichem, the last significant conference of 2021, has just ended. Traditionally held every five years, these meetings usually bring thousands of visitors from Pacific Rim countries to Honolulu. They are planned years in advance: symposia proposals were due in early 2018. Pacifichem 2015 saw the first symposium dedicated to FBLD, and that was so popular that a few of us planned one for 2020. The conference organizers decided to postpone the 2020 meeting in the hope that we could all meet in person. But SARS-CoV-2 had other plans, and instead of meeting in Hawaii we met on Zoom.

 

Time zones were challenging. Four-hour sessions started in the morning or evening Hawaiian time, which translated to 02:00 in Shanghai or 23:00 in Boston, respectively. In contrast to other virtual meetings almost all the presentations were live and not recorded, which meant that you only had one chance to see a talk.

 

Despite these challenges and universal Zoom-fatigue, the event came off quite well. With more than two dozen presentations I won’t attempt to cover everything but will instead just touch on a few themes.

 

Methods

Quite a few talks focused on methods, with NMR being especially well-represented. The symposium started with Will Pomerantz (University of Minnesota) discussing Protein-Observed Fluorine (PrOF) NMR, in which fluorinated amino acids are introduced into proteins. We’ve written about this previously, including Will’s longstanding interest in assessing shapely fragments. After reading about Mads Clausen’s fluorinated Fsp³-rich library, Will established a collaboration and has found 8 hits from 79 fragments screened against BET bromodomain proteins. He has also been able to optimize potent leads selective for either the BD1 or BD2 domains of BRD4.

 

Scott Prosser (University of Toronto) is also using NMR to study fluorine-labeled proteins, in this case GPCRs. And Michael Overduin (University of Alberta), one of the symposium organizers, is also studying membrane-bound proteins using NMR techniques.

 

On the extreme side of spectrometers, Chojiro Kojima described the 950 MHz NMR at Osaka University. This enables a ¹H-¹³C HSQC experiment on protein as dilute as 0.2 micromolar, which could be valuable for insoluble or hard-to-purify proteins. The facility is open to international collaborators. Chojiro also described isotopically labeling proteins with transglutaminase and ¹H{¹⁹F} STD NMR, which works even when the fluorine peak itself is broadened to invisibility.

 

But you don’t need a big magnet to do good science. Brian Stockman’s group at Adelphi University is composed entirely of undergraduates who use substrate-detected NMR to follow enzymatic reactions to find inhibitors of neglected parasitic infections.

 

All techniques can give false positives, and NMR can be very effective at weeding these out. As we described two years ago Steven LaPlante (NMX) has been developing methods to rapidly identify aggregators and has been assembling something of a taxonomy; more later.

 

But the conference was not all NMR all the time. Rebecca Whitehouse (Monash University) described a 91-compound “MicroFrag” library consisting of fragments containing 5-8 atoms, “somewhere in the land between solvents and fragments.” NMR and crystallographic screens of the difficult antimicrobial target DsbA gave very high hit rates, and both techniques successfully identified the large but shallow substrate-binding groove. In contrast, screening actual solvents or using the well-established FTMap computational approach did not clearly identify this groove.

 

The push in crystallography is towards increased speed, and Debanu Das described the high-throughput platform at Acclero BioStructures, which is capable of screening 1000 fragments per week, similar to XChem. But if even that is too slow for you, Marius Schmidt (University of Wisconsin-Madison) described mix-and-inject experiments using the European X-ray free-electron laser (XFEL). Much of the focus with this technique has been on high-speed enzymology, but since 100 datasets can be collected in 10 hours it can be used for high-throughput crystallographic screening too. An upgrade next year will increase this to 1000 datasets in 3 hours, though the resulting petabytes of data will no doubt create headaches for IT departments.

 

It’s not enough to find hits, you need to figure out what to do with them, and symposium organizer Martin Scanlon (Monash University) discussed a computational approach (GRADe, similar to Fragment Network) as well as the experimental (REFiL) approach we’ve discussed previously. Across 9 projects the techniques were successful at improving affinity, in some cases from unmeasurable levels.

 

Covalent Fragments

Several talks focused on covalent FBLD. Alexander Statsyuk (University of Houston) proposed five rules for covalent fragments: 1) ease of synthesis; 2) non-promiscuous electrophiles; 3) intrinsic reactivity should be the same within the library; 4) a given library should use the same electrophile; and 5) the electrophile should be on the end of the molecule with a minimal linker connecting it to the variable fragment. Some of these make sense, but it would have been fun to debate others over Mai Tais.

 

Dan Nomura (UC Berkeley) described using covalent fragments in chemoproteomic experiments, where he has identified more than 100,000 potentially ligandable hotspots in more than 16,000 human proteins. Among other applications, this allows him to make bifunctional molecules to bring two proteins together. A clear application is PROTACs, where the electrophilic fragment targets an E3 ligase, but he also described targeting the deubiquitinase OTUB1 to stabilize proteins.

 

Earlier this year we celebrated the approval of the KRAS^G12C inhibitor sotorasib. This target had long resisted drug discovery efforts; Ratmir Derda (University of Alberta) evocatively mentioned “waves and waves of medicinal chemists washing off its shore for 30 years.” Success was finally enabled using disulfide Tethering, and David Turner (Frederick National Laboratory) is now using this approach to interrogate nearly every surface-exposed residue by systematically mutating them to cysteines and screening against more than 1000 disulfide-containing fragments. He is well over half-way through the 85 mutants, and the resulting dataset should be valuable not just for drug discovery but for understanding molecular interactions.

 

Success Stories

With more than 50 drugs in the clinic derived from fragments, there were several success stories. Masakazu Atobe (Asahi Kasei) presented the discovery of the potent PKCζ inhibitors we wrote about here. And Chaohong Sun (AbbVie) described inhibitors of TNFα (see here), emphasizing the importance of robust biophysics and early committed chemistry.

 

Finally, Emiliano Tamanini (Astex) presented a nice fragment-to-lead effort to find a selective inhibitor of HDAC2. Despite some successes, histone deacetylase inhibitors tend to be non-specific and come with side effects. Emiliano described a fragment screen that identified a new metal chelator and used fragment merging to develop a molecule capable of crossing the blood-brain-barrier.

 

These last two stories in particular are examples of pursuing difficult targets, another theme throughout the conference. When asked about the challenges of targeting cancer-resistance-causing glucuronosyltransferases, Katherine Borden (University of Montreal) responded, “if you don’t try, where will you be?”

 

Bright words for these darkling days.

Nineteenth Annual Discovery on Target Meeting

Cambridge Healthtech Institute held its annual Discovery on Target meeting last week. For the first time the event was hybrid, with slightly fewer than half the attendees in Boston and the rest online, and I’m happy to report that it was quite successful. In-person attendees were required to show proof of vaccination against COVID-19, and masks and social distancing guidelines were observed. Ten of the individual tracks were hybrid, while four were virtual only. However, even in these cases it was valuable to attend in person; after one vendor presentation I immediately went from my hotel room to the exhibit hall to find out more.

 

For many of us this was the first in-person conference we had attended in nearly two years, and the return to some semblance of normalcy. At the same time, the fact that in-person talks were broadcast opened the conference to people unable to travel. One of the most active Q&A participants in one track was in Singapore, despite the 12 hour time difference.

 

Another nice feature of the virtual or hybrid model is reduction in FOMO; if you find it difficult to choose between the seven concurrent talks you can watch some later. But, as our 2020 poll showed, speakers may be less forthcoming with newer, more speculative results in a recorded format.

 

With the heavy focus on biology there seemed to be fewer “conventional” fragment stories, though Lars Neumann (Proteros) did discuss the identification and optimization of a kinase inhibitor that does not interact with the hinge region. Novel targets were represented in work from Harald Schwalbe (Johann Wolfgang Goethe University), who described fragment screens against RNA; I’ll post more on this later this month.

 

We’ve previously discussed the COVID Moonshot Consortium to rapidly discover drugs for SARS-CoV-2. Annette von Delft (Oxford University) provided an update, noting that fragments from a crystallographic screen have been advanced to compounds with mid-nanomolar biochemical and cellular activity. DMPK properties are reasonable, though this is an area of continued optimization. Annette mentioned the goal is to enter clinical development in 2023. Progress has been accelerated by the crowd-sourced nature of the initiative, with nearly 40 groups and 150 individuals working together. She also noted that many of the molecules are active against other coronaviruses.

 

The main series being advanced by the COVID Moonshot are noncovalent inhibitors of the SARS-CoV-2 main protease M^Pro. However, covalent molecules against this target are also moving forward. Matthew Reese described Pfizer’s oral PF-07321332, which is currently in several phase 3 trials. The program began on March 16 of last year and the clinical compound was first synthesized just four months later. Clinical trials began in February of this year, a mere 11 months after the program began. This is astonishingly rapid, though the researchers did benefit from previous work on SARS-CoV-1 and even earlier work from the 1990s on rhinovirus inhibitors. It is worth re-reading Glyn Williams’ 2020 discussion of HIV protease inhibitors for more historical context and insights.

 

Although PF-07321332 did not come from FBLD, fragments capable of forming covalent bonds were well represented. We’ve previously discussed fully-functionalized fragments (FFFs, or PhABits), which in addition to having a photoreactive group also contain an alkyne handle so that any target they bind can be captured and identified. Aarti Kawatkar and Jenna Bradley described using these at AstraZeneca to identify new targets. They’ve constructed a library of just under 500 FFFs and are using these to do phenotypic screening, particularly in hard-to-get cells such as primary tissue samples. They are also making the FFF library available through their open innovation initiative.

 

Fully functionalized fragments are just one flavor of covalent fragments. Indeed, unlike the light-activated warhead of FFFs, most covalent fragments have a moiety that reacts selectively with amino acid residues such as cysteines. Steve Gygi (Harvard) and Dan Nomura (UC Berkeley) both described covalent screening in cells to identify starting points against challenging targets. The approach is also gaining traction in industry; Heather Murrey described how Scorpion is using covalent fragments, and noted that Vividion (mentioned here) was recently acquired by Bayer for up to $2 billion.

 

A prominent recent success story from covalent fragments is sotorasib, which was approved earlier this year to treat certain non-small cell lung cancer patients whose tumors carry the G12C mutant form of KRAS. Sotorasib binds to a mostly cryptic pocket, and the protein itself has low ligandability. To improve the odds of finding new fragments, Mela Mulvihill described how she and her colleagues at Genentech have developed antibodies that stabilize the so-called Switch II loop in an “open” conformation more accessible to small molecules. An SPR-based fragment screen in the presence of the antibody led to more than twice as many hits, many of which could bind more tightly than without the antibody. Darryl McConnell (Boehringer-Ingelheim) also described using fragment-based methods to pursue KRAS, including mutants other than G12C.

 

In addition to inhibitors, Darryl also described bifunctional molecules that selectively cause degradation of KRAS by bringing it to the proteasome via E3 ligases. In his opinion PROTACs are “the best thing since sliced bread.” PROTACs and targeted protein degradation were in fact the subject of two tracks that spread across all three days of the conference, and were also covered in a pre-conference short course taught by Stewart Fisher (C4 Therapeutics) and Alexander Statsyuk (University of Houston). Here too fragments are playing an increasing role; in a second talk Dan Nomura described how he has been using chemoproteomic fragment approaches to identify ligands for E3 ligases.

 

The recent excitement around PROTACs is probably justified, but as our post last week noted, new technologies are not necessarily fast or inevitable. PROTACs were first described in 2001; Adam Gilbert (Pfizer) puckishly described them as a “20-year overnight success story.” But by the end of this year there will be roughly a dozen PROTACs in the clinic, with more likely to join them soon.

 

I’ll end on this positive note, but welcome your thoughts on science or experience with hybrid conferences. I look forward to seeing you at one in the near future!

Fragment events in 2021 and 2022

Yes, 2021 is actually half over.

COVID-19 remains rampant throughout much of the world, but billions of vaccinations are reducing transmission and severity. With luck - and continued efforts - the worst of this epidemic may be behind us.

Among the many things to look forward to are in-person conferences, which are starting to return. But since travel is not possible for everyone (even pre-SARS-CoV-2), several of the upcoming events will be hybrid, with opportunities to attend either physically or virtually. Hope to see you at one.

2021

September 27-30: CHI’s Nineteenth Annual Discovery on Target returns to the real world - or at least Boston. As the name implies this event is more target-focused than chemistry-focused, but there are always plenty of FBDD-related talks. You can read my impressions of the 2020 virtual event here, the 2019 event here, and the 2018 event here.

December 16-21: What better place to say goodbye to COVID than Hawaii? Postponed from last year, the second Pacifichem Symposium devoted to fragments will be held in Honolulu on December 18 and 19. Pacifichem conferences are normally held every 5 years and are designed to bring together scientists from Pacific Rim countries including Australia, Canada, China, Japan, Korea, New Zealand, and the US. Here are my impressions of the 2015 event.

 

2022

March 27-29: The Royal Society of Chemistry's Fragments 2022 will be held in the original Cambridge. This is the eighth in an esteemed conference series that usually alternates years with the FBLD meetings. You can read my impressions of Fragments 2013 and Fragments 2009.

 

April 18-21: CHI’s Seventeenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, returns to sunny San Diego. This is part of the larger Drug Discovery Chemistry meeting. You can read impressions of the 2021 virtual meeting here, the 2020 virtual meeting here, the 2019 meeting here, the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting here, here, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here.

 

Know of anything else? Please leave a comment or drop me a note!