Novartis’ HRO761 is an oral allosteric WRN helicase inhibitor, aimed at treating MSI-high and dMMR tumors. This article details the discovery of HRO761 and highlights the importance of selecting appropriate assays during early HTS as well as transferable medicinal chemistry strategies to optimize permeability and solubility through the modulation of LipE, neutral TPSA, chameleonicity, and non-classical zwitterions. It also explores the X-ray structure of HRO761 bound to WRN, how it differentiates from Vividion's VVD-214, its preclinical activity, clinical status, chemical synthesis, and more!

GDC-1971 is an orally bioavailable allosteric inhibitor of the SHP2 phosphatase discovered by Relay Therapeutics, and in clinical development by Genentech both as a monotherapy and in combination with several anticancer therapies. SHP2 inhibitors are being hotly pursued since they may combine with numerous classes of clinically important agents. This article provides a primer on SHP2 as an oncology target, the disclosed molecules in the space, how RLY-1971 was identified, and what the industry is watching for.

ORIC-944 is a second-generation, orally bioavailable PRC2 inhibitor, targeting the allosteric EED subunit. EZH2 inhibitors typically require frequent dosing due to poor drug-like properties. This article describes the previously undisclosed structure-based design of ORIC-944 into a potential best-in-class PRC2 inhibitor with enhanced solubility, metabolic stability, and prolonged clinical half-life compared to EZH2 inhibitors. It also highlights ORIC-944's capability to reprogram refractory, AR-independent prostate tumors to an AR-dependent state, the synthesis, clinical data, and more!

Nested Therapeutics’ lead asset, NST-628, is an oral, brain-penetrant pan-RAF–MEK non-degrading molecular glue that lacks paradoxical pathway activation. Read the full article to learn about NST-628’s fascinating mechanism of action preventing paradoxical pathway activation, how it differentiates from other RAS/RAF/MAPK pathway inhibitors, the likely molecular origin, preclinical profile supporting clinical development, why this might be an ideal combination partner, and why this molecule is a big deal.

RMC-6236 is a non-covalent pan-RAS(ON) inhibitor from Revolution Medicines, which shows remarkable efficacy in tumors driven by RAS mutants that were previously considered “undruggable,” such as G12V/D/A/S, G13X, and Q61X. RMC-6236 exerts its action via a “tri-complex” mechanism, gluing RAS to the ubiquitously expressed chaperone protein, cyclophilin A. Our in-depth article covers the presentation given at the AACR 2024 meeting, which outlines the discovery and preclinical profile of RMC-6236 as well as the latest clinical updates.