Drug Hunter reposted this
A Chameleonic Allosteric Inhibitor of WRN Helicase for MSI-High and dMMR Tumors | https://lnkd.in/gfZGTn_Z Novartis' HRO761 is an oral allosteric inhibitor targeting WRN helicase for tumors exhibiting microsatellite instability (MSI) or deficient mismatch repair (dMMR) currently in a Ph. I trial. WRN has emerged as a critical synthetic lethal target in MSI cancers, which are prevalent in colorectal, gastric, endometrial, and ovarian cancers. Despite the high response rate of MSI cancers to immune checkpoint inhibitors, many patients face resistance. The notoriously challenging-to-target WRN could become the first drugged helicase following Novartis and Vividion Therapeutics, Inc.'s clinical foray into the area. Notably, many other teams are actively developing their own WRN inhibitors making this a highly competitive area to watch in the years ahead. This article details the fascinating discovery story of HRO761 and highlights the importance of selecting appropriate assays during early HTS discovery 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 unique X-ray structure of HRO761 bound to WRN, how it differentiates from Vividion Therapeutics, Inc.'s VVD-214, its preclinical activity, clinical status, chemical synthesis, and more! Link | https://lnkd.in/gfZGTn_Z
Director of DMPK at Agios Pharmaceuticals
2wchameleonic and chameleonicity - who first coined these terms?