I discuss a permeable-first strategy to evolve a macrocyclic peptide PPI hit into a cell-active lead. It is the first in vivo demonstration of cyclin A/B RxL inhibitors as a new class of targeted anti-cancer agents.

We have developed methods for nanoscale chemical synthesis and high-throughput screening of combinatorial libraries of tens of thousands of small, non-polar cyclic peptides that can passively cross membranes. After initial proof-of-concept screens against proteases, we have applied the approach to intracellular protein-protein interaction targets and recently identified cell-active inhibitors.

We have developed an integrated computational and experimental approach to identify allosteric sites and inhibitors in protein-protein interactions, specifically targeting BCL-2 family proteins. My talk will highlight structural, biochemical, and cellular techniques used to uncover novel allosteric binding sites, providing insights into their functional relevance. A particular focus will be on the discovery of allosteric inhibitors for the anti-apoptotic protein BCL-XL, which holds therapeutic potential in modulating apoptosis in various cancers. This approach may offer a versatile strategy for targeting protein-protein interactions within the BCL-2 protein family and beyond, enabling the development of selective inhibitors.

SARM1 is a highly oligomeric NAD hydrolase implicated in neuronal cell death after injury. Well established small molecules exist that inhibit SARM1 activity, via a base-exchange mechanism that prevents further hydrolysis. Here, we present extensive MOA characterization of base-exchange dependent SARM1 inhibition via biophysical and biochemical methods, in addition to discovery of an unexpected secondary MOA driven by inter-domain interactions with undesired observations.

VCP/p97 is a homohexameric AAA+ ATPase that is directed by more than 30 adaptor proteins to unfold a broad range of cellular targets, mediating their degradation. Our lab seeks to direct biology by developing conformational modulators of VCP that can stabilize interactions with subsets of adaptor proteins that share a conformational preference. To enable this project, we have engineered tools that report on VCP structure using changes in FRET efficiency.

A large amount of the proteome remains undrugged. Rapafuysn’s platform of non-degrading molecular glues is uniquely positioned to target intracellular proteins and the cytosolic side of transmembrane proteins. The company’s platform of RapaGlues takes advantage of the exclusively cytosolic residing FKBP12 to form ternary complexes with disease target proteins. The presentation will describe successful hit campaigns for hard to drug targets and the strategy used for optimizing ADME properties of RapaGlues to give drug like molecules.

We designed a series of tri-complex small molecule inhibitors targeting the GTP-bound, active state of RAS (RAS(ON)). The inhibitors bind non-covalently to an abundant intracellular protein, cyclophilin A (CypA) which then selectively engages RAS(ON) and sterically prevents RAS from interacting with its downstream effectors. We also describe mutant selective inhibitors that covalently engage RAS(ON) G12C, G13C and G12D respectively. Our RAS(ON) multi-selective inhibitors can also inhibit variants of KRAS, NRAS, and HRAS.

The KRAS protein, mutated in 20% of human cancers, was long considered undruggable. Recent breakthroughs led to the first KRAS G12C inhibitors, but need still persists for targeting other mutations. In collaboration with the Ciulli group we identified ACBI3, a KRAS degrader with high potency against a variety of KRAS mutations in vitro and in vivo. These promising preclinical results mark a significant stride towards broad-spectrum KRAS-targeting modalities.

KRAS mutations are among the most prevalent and challenging targets in cancer. While only the KRAS G12C mutation currently has clinically approved therapies, there is a critical need for effective and durable treatments across all KRAS-driven cancers. We will present our success in identifying a development candidate that degrades all tested KRAS mutants, showcasing its potential as a promising therapeutic strategy for cancer treatment.

Once viewed undruggable, frequently mutated oncogene KRAS has led to the recent approval of two KRAS^G12C small molecule covalent inhibitors targeting the inactive GDP-bound (OFF) state. Patient benefit has fallen short with these first-generation inhibitors due to innate or acquired resistance driven by upregulation of the activated GTP-bound (ON) state of KRAS^G12C. We present the discovery of potent dual inhibitor FMC-376 targeting both active and inactive forms of KRAS^G12C.

Covalent inhibition of the KRASG12C oncoprotein has emerged as a promising therapeutic approach for the treatment of NSCLC. A covalent DEL screening was designed to screen approximately 16 million chemically diverse compounds against KRASG12C. The hit identification through this efficient screening followed by structure-based optimization allows for the discovery of a series of structurally novel, potent, and selective covalent inhibitors of KRASG12C with good pharmacokinetic profiles and promising pharmacodynamic effects.

I present my Ras GTPases (mainly Ral and KRAS) work where I used fragment-screening to develop covalent inhibitors that react with tyrosines. A tyrosine-based covalent approach expands the number of KRAS-origin cancers that can be targeted because only 10% of KRAS genes have the G12C mutation. I also discuss our progress with covalent inhibition of Ral GPTase using tyrosine and will present a unique KRAS structure that I recently published.