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!