Whereas covalent drugs were once considered risky for indications other than cancer due to the potential for idiosyncratic drug-induced liver injury and other toxicities, concerns appear to have softened as an increasing number of non-oncology covalent inhibitor programs have achieved successful outcomes. Here we highlight several recent anecdotes in covalent inhibitor drug discovery that seem to reflect these changing attitudes, including billion-dollar acquisitions and approvals outside oncology, and a few modern examples that showcase the increasingly rich science in this area.

Kymera's KT-474 is the first oral degrader to demonstrate activity in clinical trials outside cancer. Sanofi recently started a Ph. II trial with the molecule in AD, restoring life to IRAK4 as an immunology target. This article highlights several reasons why Kymera’s KT-474 program is scientifically notable, including but not limited to differentiation from small molecules, potential competitiveness with biologics, the first reported Cryo-EM ternary complex of a heterobifunctional degrader, and more. The molecule will likely be considered a modern “classic in drug discovery” for some time.

In 2022, Turning Point Therapeutics ($TPTX) was acquired by BMS for a whopping $4.1 billion in cash. In November 2023, the most advanced molecule from Turning Point, repotrectinib, was approved for the treatment of ROS1+ NSCLC. This article explores the science behind repotrectinib, what made Turning Point so valuable, how we know, and what's next. [...]

Chugai’s PCO371 is an oral, biased agonist and "molecular wedge" of the class B GPCR, PTHR1, that first entered development for hypoparathyroidism in 2015 (NCT02475616). While Class A GPCRs, which typically have compact ligandable pockets are the most common targets for approved drugs, Class B GPCRs like PTHR1, GLP-1R, and CGRP are notoriously difficult to drug since they normally bind large peptides with long transmembrane tunnels that are not easily bound by small molecules. This article explains what makes PCO371 a big deal for GPCR drug discovery.

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here we have compiled a table of >70 additional molecules that were of interest in October 2023 but we did not have space for in MOTM. A few highlights are also discussed, including Novartis’s Werner helicase (WRN) inhibitor, APJ agonist AMG985 molecular glue degrader golcadomide, and more in the full article.