IAG933 is Novartis’ potential first-in-class small molecule inhibitor of the PPI between YAP/TAZ and TEAD, currently in a Ph. I trial for solid tumors with Hippo pathway alterations. This case study not only highlights a fascinating mechanism of action but also serves as an excellent example of how to leverage structural data to inform hit selection and guide lead optimization, how to employ multiparameter optimization to circumvent cardiotoxicity liabilities, and how to redirect metabolism.

Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

Revumenib (Revuforj®) is approved by the FDA as an oral, first-in-class menin-MLL interaction inhibitor for acute leukemia (AL). Since inhibition of the menin-MLL fusion protein interaction is selective for AL with a KMT2A translocation, it does not compromise normal hematopoietic function. This article covers the background, optimization and clinical development that has led to the approval of this groundbreaking new drug in a hard-to-treat indication.

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor from Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.

Sovleplenib (HMPL-523) is an orally bioavailable Syk inhibitor being developed by HUTCHMED and is currently in Ph. II and Ph. III clinical trials for several autoimmune diseases. Derived from an HTS hit and SAR optimization, the discovery story of sovleplenib serves as an excellent case study on how to design a next-generation Syk inhibitor devoid of off-target kinase activity, mitigated hERG activity, and more.