Eighteenth Annual Fragment-Based Drug Discovery Meeting

Last week the CHI Drug Discovery Chemistry (DDC) meeting was held in San Diego, and it was the largest ever, with more than 850 participants, 87% of whom attended in person, up from 70% last year. I won’t attempt to cover all twelve tracks, but will just touch on some of the main themes.

 

Covalent fragments

Brent Martin kicked off a session devoted to covalent modifiers by describing the in-cell proteome-wide covalent ligand discovery done at Scorpion Therapeutics. Brent emphasized the importance of measuring k_inact/K_i to characterize compounds, and he went so far as to say he would recommend rejecting papers that report only IC₅₀ values. He emphasized some of the challenges finding low-affinity fragments (with high K_i values) that are not overly reactive. But Upendra Drahal (Amgen) noted that sotorasib has only weak affinity (K_i = 86 µM) but a high k_inact (0.85 s^-1) for the G12C mutant form of KRAS, despite being quite stable against glutathione. High reactivity is fine, as long as it is highly selective reactivity.

 

Jeffrey Martin (Biogen) spoke about covalent fragments applied to neuroscience, including targets for Alzheimer’s (tau) and Huntington’s disease. And in two separate talks Dan Nomura (UC Berkeley) provided numerous examples of finding covalent fragments against a variety of targets, including cMYC and E3 ligases (more on those below).

 

Keynote speaker Michelle Arkin (UCSF) described using disulfide Tethering to find reversible covalent binders of caspase 6 that were subsequently optimized to cell-active irreversible inhibitors. She provided an evocative visual metaphor of proteins participating in an English country dance, moving from partner to partner in a dynamic yet choreographed fashion. The most popular dancers are the 14-3-3 proteins, which act as hubs mediating binding to hundreds of other proteins. Michelle has found stabilizers of some of these interactions, which could shut down aberrant disease signaling.

 

Covalent ligand discovery is best done with mass spectrometry, and two talks revealed useful new methods. Jim Nonomiya described an approach he and his Genentech colleagues developed called CoMPAS, covalent mapping by peptide attenuation screening. This method uses an isotopically labeled peptide as an internal standard to assess disappearance of covalently modified peptides from enzymatically digested proteins. Sensitivity can be much better than for intact protein mass spectrometry, allowing lower consumption of scarce recombinant protein. Depending on the type of setup, throughput can also be higher.

 

Throughput is the name of the game in a method presented by Nate Elsen (AbbVie) called IR-MALDESI-MS. The home-built system uses a laser to gently ionize aqueous solutions in 384-well plates before running them through an electrospray mass spectrometer. The system can analyze up to 20 samples per second, including intact proteins.

 

Non-covalent fragments

Turning to non-covalent methods, Rod Hubbard (Vernalis) provided an update of the PAC-FragmentDEL approach which we highlighted last year. DNA-encoded libraries can be mind-bogglingly large, with more than a trillion molecules at Hitgen. The fragment set is much smaller, at just 130,000 members, but this is still two orders of magnitude larger than a typical fragment library. (Speaking of which, please make sure to fill out our library survey on the right-hand side of the screen if you haven’t already done so.) This increased chemical diversity increases the odds of finding rare molecules, such as molecular glues that bind to protein complexes rather than individual components.

 

Success stories are always plentiful at conferences. Timo Heinrich (EMD Serono) described using SPR to identify fragments that were optimized to orally bioavailable inhibitors of the anti-cancer target TEAD1, which we wrote about here. Mihir Mandal (Merck) described the use of fragment concepts in the development of clinical candidates targeting metallo-β-lactamases, an important cause of antibiotic resistance. Chris Smith described Mirati’s discovery of inhibitors against the anti-cancer target PRMT5/MTA, one of which has gone into the clinic (see here and here). And Tanweer Khan traced the origins of renin and plasmepsin inhibitors to work on the aspartyl protease BACE1 at Merck, which we wrote about here.

 

Sometimes we learn just as much from projects that don’t move forward, as illustrated in a nice talk by Haihong Wu. He and his AbbVie colleagues were interested in the tau protein, which is intrinsically disordered, making structure-based design difficult. Although a two-dimensional NMR screen identified several dozen fragment hits, these were hard to optimize, with sharp, non-linear SAR. Perhaps the covalent binders we mentioned above will be more advanceable.

 

Targeted protein degradation

Targeted protein degradation and induced proximity were major themes of the conference. We speculated several years ago that FBLD could be useful here, and this has turned out to be abundantly true.

 

E3 ligases attach ubiquitin to other proteins, marking them for degradation. More than 600 exist in the human genome, but only a handful have been co-opted for targeted protein degradation, and everyone is racing to find new and better ligands for the unexplored E3 ligases. Mary Matyskiela described how she and her colleagues at Neomorph are using fragment screening to identify such ligands. She said they have been able to use cryo-electron microscopy to guide structure-based design.

 

Dan Nomura’s second talk focused on finding ligands against E3 ligases, including UBE2D and RNF126. For both of these proteins small covalent ligands seem to be generally useful for causing degradation of target proteins, and because the chemical structures have been disclosed it will be fun to see them explored in more systems.

 

A significant focus for targeted protein degradation is to find ligands for E3s that are restricted to specific tissues or tumors. Steve Fesik (Vanderbilt) described using SAR by NMR to find ligands against three E3 ligases, including one not expressed in the heart, which could avoid cardiotoxicity. Steve also described using SAR by NMR to find nanomolar binders for β-catenin. These are being used to make degraders for this anti-cancer target.

 

Many of the molecules used for targeted protein degradation are well beyond conventional rule-of-five space as they contain binding moieties for the target of interest as well as an E3 ligase. Reflecting on his forty-year career as a medicinal chemist at Bristol Myers Squibb, keynote speaker Nicholas Meanwell noted that a beautiful drug is one that helps patients, not one that fits a set of metrics. For small molecule therapeutics, he observed, “the opportunities have never looked better.”

 

We’ll end on this note, but please feel free to leave comments about your highlights. And mark your calendar for April 1-4, when DDC returns to San Diego.