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.

Artificial intelligence has great potential for impact in drug discovery, but only if AI tools are used carefully, with an understanding of their strengths and weaknesses. This presentation will focus on how AstraZeneca applied REINVENT (for generative design) and AiZynth (for retrosynthetic analysis) to an immuno-oncology project, HPK1. Over several years, two AI-assisted campaigns were undertaken, one focused on hit discovery and the other on scaffold-hopping. The latter ultimately led to the identification of a backup series for the program. The HPK1 case study informed the development of REINVENT and served as a valuable early experience in AstraZeneca for how best to integrate AI tools with human knowledge and creativity.

The emergence of heterobivalent degraders as a clinically relevant therapeutic modality has led to increased medicinal chemistry focus on design for the oral route of administration. However, some target classes require the degrader to access the protected CNS compartment. This presentation will review beyond rule of 5 oral bioavailability design principles, set the context for and describe design principles that correlate with exposure in the CNS compartment in rodents, which deliver CNS pharmacodynamic and efficacy across a number of case studies.

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.

Adenosine Monophosphate-activated Protein Kinase (AMPK) is a heterotrimeric complex that plays an essential role in cellular energy regulation to promote downstream processes such as fatty acid synthesis and mitochondrial biogenesis, making AMPK a compelling biological target for a multitude of indications. In this presentation, we’ll detail the discovery story of PF-07293893, a novel and selective activator of AMPK gamma 3 for the treatment of heart failure. Our initial lead matter was discovered from a fragment screen and was advanced to provide in vitro tool compounds, but which faced fundamental ADME issues which limited in vivo investigation. We overcame this challenge through a creative medicinal chemistry strategy to completely overhaul our structure, providing a new series which displayed activity in vivo. From these new leads, the team utilized structure based drug design and medicinal chemistry strategies such as conformational constraint to improve potency, while also working to remove undesirable off-target activity. This work, in combination with improvements in ADME properties ultimately led to the identification of PF-07293893 as a clinical candidate for the treatment of heart failure.

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.

Inhibition of negative feedback mechanisms regulating the MAPK signaling pathway limit the utility of kinase inhibitors as monotherapies in KRAS-driven cancers. In seeking new ways to address such limitations, functional genomics screens conducted at Tango Therapeutics identified heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) as a synthetic lethal pairing with MEK inhibition in KRAS-mutant non-small cell lung cancer. HS2ST1 catalyzes a key sulfation step in the biosynthesis of heparan sulfate proteoglycans (HSPGs), which contribute to FGFR-dependent reactivation of the MAPK pathway. Genetic and biochemical studies confirmed that HS2ST1 enzymatic activity is essential for its synthetic lethal effect. Given the paucity of reported inhibitors for this enzyme class, we embarked upon a drug discovery campaign to identify inhibitors of HS2ST1. Our efforts at optimizing a micromolar screening hit into potent, selective, cell-permeable inhibitors were informed by ligand-based design and by the first crystal structures of human HS2ST1. Ultimately, these efforts led to first-in-class inhibitors of HS2ST1 that may serve as useful chemical probes of the role of 2-O-sulfation in growth factor signaling and cancer biology.