Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.

Last year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Reata’s lead molecule, omaveloxolone (SKYCLARYS®), an oral, reversible covalent inhibitor of the E3 ligase KEAP1, became the first drug approved for Friedrich’s Ataxia. Omaveloxolone was previously highlighted as a Molecule of the Month in July 2023. Now, this 2023 Molecule of the Year nominee reflects a historic milestone for neurological drug discovery. This comprehensive explainer dives into Nrf2 target rationale, how it works, how the drug was discovered, its synthesis, and why it’s a big deal.

Xanamem® is Actinogen Medical's cortisol-blocking drug targeting the 11β-HSD1 (11β-hydroxysteroid dehydrogenase) enzyme.

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2. This Featured Case Study reviews how it was discovered, how it works, and why it matters.

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant PI3Kα (phosphatidylinositol-3 kinase α) targeting a cryptic pocket near the ATP-binding site. PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects including hyperglycemia and rash.