Deciphera’s DCC-3116 is an oral ULK1/2 inhibitor targeting the autophagy pathway, a key mechanism of tumor survival and resistance to targeted therapy. Currently in two open-label Ph. I/II trials as a monotherapy and in combination with RTK pathway inhibitors, the structure and discovery of this first-in-class compound were recently presented at the ACS Spring 2024 meeting.

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!

AstraZeneca has joined the race to gain approval for a first-in-class, orally bioavailable selective inhibitor of CDK2 with AZD8421, which was recently disclosed at the AACR San Diego 2024 “New Drugs on the Horizon” series. CDK2-selective inhibitors are a hot area right now, with their promise to overcome the resistance against approved CDK4/6 inhibitors. Read the full case study to learn about the CDK2-selective competitive landscape, the structural and kinetic data which underpin AZD8421’s CDK-selectivity and the preclinical activity data which has propelled it into the clinic.

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.

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.