Over the last few years, numerous computational tools have appeared in the literature to model bifunctional degraders. Generally, these studies focus on predicting the structures of degrader-containing ternary complexes, with only occasional investigations into predicting the efficacy of potential degrader designs. In this talk, we will discuss recent results with our well-established ternary complex modeling tool, Method 4B, focused entirely on its ability to score potential degrader designs. This talk will establish best-practices for using Method 4B across diverse systems, focusing on the level of precision that can be expected for prospective degrader screening campaigns.

MOMA-341 is a chemically distinct, potent and selective clinical stage inhibitor of WRN that acts through covalent ligation. In tumors with high DNA microsatellite instability (MSI-H), WRN is required for survival. Therefore, inhibition of WRN has the potential for therapeutic benefit, sparing normal tissues where WRN is not essential. MOMA Therapeutics’ KNOMATIC platform is focused on the discovery of inhibitors for highly dynamic proteins (e.g. ATPases) leveraging deep structural annotation alongside tailored screening techniques. Employing a DNA-encoded library screen that interrogated multiple putative WRN conformations, we discovered a novel hit class of reversible, allosteric, ATP-competitive inhibitors that induce an inactive conformation of WRN. Leveraging the presence of cysteine 727 in the binding pocket, covalent inhibitors were designed to achieve high occupancy and potency. Key to the success of the series optimization was precise refinement of covalent warhead trajectory and improvement of reversible binding affinity to drive high k_inact/K_I while maintaining warhead stability. Due to the highly flexible binding pocket, scaffold rigidification in the bioactive conformation was necessary to improve target engagement. Optimization of potency and ADME properties in this rigidified background, guided by in silico prediction methods to maximize modeled in vivo target occupancy, led to the discovery of clinical candidate MOMA-341. MOMA-341 demonstrates tumor regression at low doses when dosed orally in several sensitive MSI-H CDX and PDX mouse xenograft models and is in Phase I clinical development.

KRAS is the most frequently mutated oncogene, driving over 20% of human cancers, including pancreatic, colorectal, lung, endometrial, and gastric tumors. Building on insights from the development of sotorasib (covalent KRAS G12C inhibitor), we leveraged structure- and property-based design to identify a new class of reversible, macrocyclic pan-KRAS inhibitors, culminating in the discovery of AMG 410. AMG 410 is orally bioavailable, highly selective over HRAS and NRAS, and has high affinity for both GTP(on)- and GDP(off)-bound states of KRAS. Non-clinical studies of AMG 410 demonstrate robust antitumor activity. AMG 410 is currently under clinical evaluation in patients harboring KRAS missense mutations or genetic amplification who have progressed on standard-of-care therapy.