Twenty-First Annual Fragment-Based Drug Discovery Meeting

Last week some 875 people attended the CHI Drug Discovery Chemistry (DDC) meeting in San Diego. I can’t do justice to the 40 or so presentations I attended over four days but can highlight some of the main themes.

 

Reversible fragments

Membrane targets such as G protein-coupled receptors (GPCRs) pose a challenge for biophysical methods, but three talks presented progress. Matthew Eddy (University of Florida Gainesville) described high-resolution magic angle spinning (HRMAS) NMR, which entails spinning isolated cellular membranes containing GPCRs at high speed (4 kHz!), which miraculously yields sharp NMR signals for bound ligands. Matthew demonstrated applications with the human adenosine A_2A receptor and weak (mM) ligands. He noted that the technique can work with native, poorly expressed proteins, though data collection times can be upwards of 30 minutes.

 

Kris Borzilleri described using ¹⁹F NMR to find ligands against an orphan GPCR at Pfizer. The 2287 fragments screened yielded 87 hits, of which 38 confirmed by SPR. SAR studies eventually yielded low micromolar ligands, but these were difficult to advance in the absence of structure (see here for a more successful example from Merck).

 

Vanessa Porkolab (Eurofins Cerep) described using the Nanotemper Spectral Shift technology to screen 826 fragments against the adenosine A_2A receptor at 300 µM, with a 9.2% hit rate. Many of these ligands stabilized the GPCR in a thermal shift assay and seven were even active (as antagonists) in a cellular assay.

 

Turning to soluble proteins, Paola Di Lello presented a case study from Genentech and Vernalis applying ligand-observed NMR to the protein phosphatase PTPN22. Subsequent protein-observed NMR revealed that most of the 16 validated hits bound to two pockets some distance from the active site. The fragments were optimized to mid-micromolar affinity but showed no functional activity.

 

And Charlotte Hodson presented the eIF4E story from Astex. As we discussed last year, this yielded a low nanomolar ligand that did not have the desired cellular effects. Charlotte noted that subsequent genetic experiments were consistent with the limited efficacy. Still, the target was sufficiently interesting that a chemical probe would have been pursued even knowing it would be high-risk.

 

Covalent ligands

Covalent approaches made appearances throughout the conference. Keriann Backus (UCLA) described chemoproteomic approaches to find cysteine-targeting ligands; she noted that gain of cysteine residues (such as G12C in KRAS) are the most common missense variants in cancer. Keriann also warned how covalent compounds can cause potentially misleading effects in cells, as she described in Nat. Chem. Biol. last year.

 

In 2021 we wrote about the SpotXplorer fragment library from György Keserű (Hungarian Research Centre for Natural Sciences). György has now prepared a PhotoXplorer library, which uses diazirine tags for photochemical screening, which we described here. The new library has produced high hit rates across a variety of targets. György also described a new sulfozone-based photoprobe that is easier to prepare than diazirines.

 

Kelly Craft recounted a DNA-encoded library (DEL) screen at AbbVie against the target BCL2A1, also known as BFL1. This produced an aldehyde-containing low micromolar binder that formed an imine with buried lysine 102. Uncomfortable progressing an aldehyde, the researchers sought to covalently engage cysteine 55, the same cysteine targeted by AstraZeneca, as we wrote about here. The progression included at least one dual-warhead molecule which was crystallographically confirmed to bind both the lysine and cysteine. The effort ultimately yielded cysteine-selective leads.

 

Earlier this year I described the dDRTC method we developed at Frontier Medicines for determining k_inact/K_I, and Svetlana Kholodar presented a nice overview of its scope and utility. My colleague Johannes Hermann spoke in more detail about our covalent technologies, particularly those using AI.

 

Chemical space and the exploration thereof

Brian Shoichet (UCSF) gave an entertaining and wide-ranging account of “directed and random walks in chemical space.” Brian has consistently been on the bleeding edge of high-throughput in silico screens, from 67,000 compounds in 2009 to 138 million molecules in 2019 to 4 billion molecules today. When docking artifacts are avoided (as we discussed here), bigger libraries consistently produce more potent hits for more targets – an observation strikingly consistent with Alex Shaginian’s in 2023 as HitGen expanded their DEL libraries from billions to more than a trillion molecules. Brian is developing methods to computationally screen the >4 trillion make-on-demand molecules now available from companies such as Enamine.

 

Direct-to-biology (DTB) approaches, which rely on microscale chemical reactions screened without purification, have become increasingly popular methods for exploring chemical space. Jack Sadowsky correctly stated that Carmot was the first company formed around this approach; we previously wrote about the role Chemotype Evolution played in the discovery of sotorasib. Jack described how Kimia, which spun out of Carmot, has continued to advance the technology, applying it to find inhibitors selective for single members of closely related kinase families.

 

Allan Jordan described how Sygnature Discovery is applying DTB in a variety of assays including microsome stability and crystallography. (We wrote about crude reaction screening by crystallography earlier this year.) Expanding beyond DTB, Allan called their platform direct-to-discovery, and discussed how it led to a preclinical candidate with STORM Therapeutics in just 18 months.

 

WuXi Apptec is also using DTB. Peichuan Zhang described starting with ligands derived from fragment and DEL screens against the E3 ligase GID4 to make PROTACs to degrade BRD4; DTB was used to explore a wide range of different linkers. And Daniel Blair (St. Jude) described using DTB and affinity selection-mass spectrometry (AS-MS) to find new molecular glues for the oncology target LCK.

 

Computers, DEL, and DTB are not the only way to explore chemical space. Last year we covered Tom Kodadek’s bead-based screening approach at University of Florida Scripps, and Tom presented two talks on the topic, one using macrocycles to find binders to difficult targets such as PTP1B and one using small molecules to find molecular glues.

 

Speaking of PROTACs and glues, plenary keynote speaker Alessio Ciulli (University of Dundee) discussed the “evolution and future of targeted protein degradation.” Alessio noted that there are >25 PROTAC degraders and >10 glues in the clinic, though these collectively target only a small number of E3 ligands, so there is plenty of opportunity for the area to expand.

 

For many of us in industry, drugs represent the most privileged points in chemical space, and these often look quite different than we assume, as Dean Brown (Jnana) noted in his recent analysis of 104 oral small molecule drugs approved by the FDA from 2020 to 2024 (which we mentioned here). Some drugs contain eye-raising moieties such as acetylenes, styrenes, N-O bonds, and nitro groups. Indeed, it is worth remembering that venetoclax, arguably the most successful fragment-derived drug, sports a nitro group.

 

But before getting too complacent, Jonathan Baell (Manas) warned about frequent hitters in libraries of FDA-approved drugs. He notes in Eur. J. Med. Chem. earlier this year that many commercial libraries are actually enriched for molecules that cause spurious biological activity. Jonathan calls on library vendors to remove particularly egregious compounds, though I’d settle for world peace.

 

I’ll close on that pleasant thought, but please feel free to comment. I hope to see you in San Diego next year April 19-22 for the twenty-second iteration of DDC.