BAY 2925976 is a novel oral ARα2C antagonist developed by Bayer for the treatment of OSA (obstructive sleep apnea), a widespread condition affecting nearly one billion people globally. Despite the availability of mechanical treatments like CPAP, poor adherence rates highlight the need for more effective interventions. BAY 2925976 demonstrated a preclinical proof of concept for ARα₂C modulation as a potential therapeutic approach for OSA. In this article, we detail the discovery of BAY 2925976, as highlighted by Michael Hahn at the ACS Fall 2024 First-Time Disclosures session in Denver, CO.

Compound 14f (Kyowa Kirin) is an oral ChemR23 inhibitor with two acidic sites. Nominated by Bryan McKibben , this article describes a scaffold hopping exercise to address the short half-life of previously described chemical matter, and the successful development of in-vivo tool inhibitors to probe ChemR23 biology in animal models of [...]

Pfizer’s ritlecitinib, a first-in-class, selective, oral covalent inhibitor of JAK3 and the TEC family of kinases, was FDA-approved in June 2023 for the treatment of severe alopecia areata. Ritlecitinib derives its JAK-family kinase selectivity from the covalent modification of a unique cysteine on JAK3. This annotation reviews the discovery of ritlecitinib, highlighting the interpretation of selectivity assays, the PK optimization, the evolution of the JAK3 therapeutic hypothesis, and how this 2023 Molecule of the Year nominee has become a classic case study for covalent drug discovery.

Remibrutinib (Novartis oral BTK-selective covalent kinase inhibitor clinical candidate)

The AstraZeneca oral RORgt inverse agonist, AZD0284 , is an inverse agonist of the nuclear receptor RORC2 (RORγt). Reviewer Chris Gampe says, “targeting the activation and function of Th17 cells has been successful for the treatment of autoimmune disease (cf. IL-17, IL-17R, IL-23 Abs). RORC2 is the transcription factor that controls Th17 [...]