Molecule Spotlight: Risdiplam, the First Approved Small Molecule Splicing Modulator for Spinal Muscular Atrophy

NaV1.8 has become an industry focal point in the pursuit of pain therapeutics thanks to the success of Vertex’s selective inhibitor, VX-548, in Ph. III clinical trials for acute pain and Ph. II results in diabetic peripheral neuropathy. Unlike opioid receptor modulation, NaV1.8 inhibition does not carry the same addiction risks in part due to its lack of expression in the brain. Following our recent review of the leading NaV1.8 inhibitor VX-548, this article provides more details on the history of target validation for NaV1.8 in pain and why this could be the new frontier for pain management.

Leniolisib is a selective PI3Kδ inhibitor that received approval in March 2023 from the FDA as a first-in-class treatment for activated PI3K-δ syndrome (APDS), a genetic immunodeficiency disorder caused by PI3Kδ activation. The leniolisib discovery program is notable for several reasons: it is a first approval for a PI3K inhibitor outside of oncology; the first approved drug for APDS; has a novel chemotype that appears to avoid safety issues that led to black box warnings seen with other PI3K molecules; and it overcame a polymorph issue with an early lead that led to inconsistent exposures.

Several multi-million dollar acquisitions or license agreements took place in November 2023 for hot drug targets, with assets from selective PARP1 inhibitors to GLP1R agonists, and others. This recent news roundup highlights the notable acquisitions by pharma companies for rights to molecules in a range of different indications, with illustrative patent examples for undisclosed structures.

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 November 2023 along with some highlights from some of our favorites below.

This article highlights million-dollar molecules that were recently in the news with related patent applications that give clues to their structures and properties. This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targeted protein degradation researchers, brain-penetrant HER2 and ROCK2 inhibitors, and MDM2 degraders.