31 August 2020

Fifteenth Annual Fragment-Based Drug Discovery Meeting

What a strange year for conferences! Everything fragment-related in the first half of the year was canceled or rescheduled. And when it turned out that postponing Drug Discovery Chemistry (DDC) from April to August was overly optimistic, Cambridge Healthtech Institute went virtual for the first time, with the meeting running last week from August 25-28. Although I was skeptical, in the end the meeting was quite successful, with more than 600 attendees – roughly three-quarters last year’s in-person attendance. 
To accommodate multiple time zones each of the parallel tracks was shorter. Days typically began around 10:00 AM EDT, which was 7:00 for me in San Francisco but midnight for folks in Melbourne. Despite this inconvenience, 40% of participants this year came from outside the US, up from 30% last year.

Most of the talks were pre-recorded, which meant that speakers could answer questions in real-time in a chat box. More importantly, the talks are available to attendees for a year, which means you can watch relevant talks from other tracks, thus relieving the FOMO inevitably experienced in meetings of this sort. It also means you can replay particularly relevant talks to your colleagues, though I wonder if this also makes speakers wary about disclosing the freshest information. The on-demand access to posters is especially useful, as it is too easy to overlook these in the usual melee. The organizers also did a nice job of trying to foster the feel of an in-person meeting, with multiple live Q&A panels, breakout sessions, and other interactive events.

There are drawbacks, chief among them the lack of spontaneous and serendipitous meetings that are one of the main benefits of in-person conferences. And of course there were technical snafus. Most talk slots were only 20 minutes, but some of the pre-recorded talks went as long as 28 minutes, forcing attendees to choose between missing part of one talk or another (or a live Q&A). Although you can fast-forward, it would be nice if you could also speed up playback speeds. And on at least one occasion the wrong talk was played, though I was able to go back and watch the correct one later.

But enough about process, what about the event itself? With dozens of talks over four days I can’t be exhaustive, so please add your thoughts to the comments.

Faster, cheaper, better.
This describes one consistent theme. Frank von Delft (Diamond Light Source) gave an update on their high-throughput crystallographic screening, which has led to > 3000 fragment hits on > 150 targets since 2016. We’ve written previously about their efforts against COVID-19, which have led to three separate sub-micromolar lead series against the viral protease MPro. This rapid progress has been enabled by crowdsourcing across more than 30 separate groups, but Frank is also moving toward crystallographic screening of crude reaction mixtures, similar to the REFiL approach described by Beatrice Chiew (Monash University, see here for a longer description). Frank hopes to make good compounds a commodity, with a 5-year vision of achieving “biologically relevant potency routinely, cheaply (£10k) and quickly (weeks).” It’s an audacious goal, and we’ll check back in 2025 to see how far the field has come.

Key to the success of these types of approaches is what plenary speaker Phil Baran (Scripps) calls “boring chemistry” that consistently works in multiple contexts. To Phil, inventing chemistry that becomes boring is a great compliment, and he showed examples of running interesting transformations in tea, beer, and wine. As the name of this blog suggests, I have a soft spot for this sort of thing, and wholeheartedly agree with his statement that “you can’t give a Nature paper to a cancer patient.”

Covalent fragments (or not)
Covalent drug discovery was also a major theme, with John McCarter (Amgen) and Matt Marx (Mirati) describing discovery of two covalent clinical compounds against an oncogenic mutant form of KRAS (see here). Dom Esposito (Frederick National Laboratory) is also pursuing KRAS using covalent Tethering. They have prepared 91 cysteine mutants and screened 18 of them against nearly 1200 disulfide-containing fragments, yielding a plethora of hits.

Alexander Statsyuk (University of Houston), Maurizio Pellecchia (UC Riverside), and Nir London (Weizmann Institute) all also discussed covalent lead discovery. Maurizio has been targeting lysine residues using sulfonyl fluorides and fluorosulfates; for the latter warhead he has been able to show reasonable pharmacokinetics in rodents. We’ve previously discussed some of Nir’s work, but here he described a nice case study against the challenging anti-cancer target Pin1 which led to potent and surprisingly selective chloroacetamides with activity in mice.

Interestingly, while chloroacetamides were the main class of MPro fragment hits, the three most advanced lead series Frank mentioned are all non-covalent. There were plenty of other nice non-covalent fragment-based success stories too, including potent selective inhibitors of the lipid kinase Vps34 (Jenny Viklund, Sprint Biosciences) and selective inhibitors of one kringle domain of apolipoprotein(a) (Jenny Sandmark, AstraZeneca).

As always, there were many talks on methods, especially during the Fifth Annual Biophysics Friday track. John Quinn (Genentech) provided a state-of-the-art update on SPR, and mentioned that they are able to screen 3000 fragments in a day or two using the Biacore 8K. This allows them to assess ligandability for new targets, and the ligandability score is predictive for how well the target performs in HTS or DEL screening.

Amit Gupta described NanoTemper’s new Dianthus instrument, which relies on the temperature-related intensity change (TRIC) of a fluorophore bound to a protein. This is similar to their MST approach though it appears to be higher-throughput, and a paper benchmarking these techniques against DSF and SPR should be coming out later this year.

Also on the subject of thermal shifts, Justin Hall (Pfizer) gave a provocative presentation on using these to determine ligand affinities. He noticed a correlation in his own research, but the prevailing wisdom held that irreversible thermal denaturation (as seen for most proteins) would not provide thermodynamic parameters. Nonetheless, perhaps because proteins are fundamentally similar (consisting as they do of chains of 20-odd amino acid residues), the temperature-dependent Arrhenius functions and activation energies of unfolding are also similar, and thus for heating rates of 4°C/minute and 100 µM ligand one can extract dissociation constants. However, he did mention that this approach is restricted to reasonably tight ligands (KD < 20 µM). Also, if a ligand binds to the unfolded state of the protein, or to multiple sites, all bets are off.

In the interest of time I’ll stop here, but if you’d like to experience a virtual conference yourself, there will be a number of good FBLD talks at Discovery on Target next month, and I hope to “see” you there. But I especially hope that in-person conferences will resume next year once our industry – and competent governments – get COVID-19 under control.


Peter Kenny said...

Hi Dan,

Measurement of affinity (needed for mapping fragment-based SAR) typically does seem to be a bit of a challenge when screening fragments crystallographically. Without the fragment-based SAR, one can’t exploit fragment-based approaches for lead generation to their full potential. As far as I can see, methods for detecting covalent fragments seem to mainly detect fragments that bind irreversibly. For some situations (e.g. tethering a warhead to a kinase inhibitor to target a cysteine that is absent in other kinases) irreversible inhibitors can work very well. However, I really don’t think targeting the catalytic cysteine of a cysteine protease is one of those situations. Irreversibility typically complicates assays (including selectivity measurement), design (inhibition is under kinetic rather than thermodynamic control) and PK/PD modelling and safety assessment. If targeting a catalytic cysteine, it is usually easy to construct structural prototypes for warheads bound reversibly to the catalytic cysteine (e.g. by editing ligand in a protein-peptidomimetic structure).

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute said...

Thanks for the really helpful review and feedback, Dan. Will try to address some of your points if we are virtual again. For those who missed the event, go to 'register' tab at www.drugdiscoverychemistry.com for on demand access at a reduced price.Or as Dan mentioned, register for upcoming www.discoveryontarget.com (Sep 16-18) also available later on demand. -- Anjani -Team Lead for Drug Discovery Chemistry