VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.

AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AZ’s clinical candidate, AZ3470. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots.

Sonrotoclax, BeiGene’s clinical-stage, orally bioavailable, next-generation inhibitor, targets both WT and mutated forms of the Bcl-2 protein by binding within a hydrophobic groove, similar to other inhibitors in its class. Explore this case study to see how sonrotoclax was rationally designed to potency against both WT and mutant Bcl-2 and address the limitations of first-generation inhibitors and more!

Inavolisib is a PI3Kα isoform-selective kinase inhibitor and monovalent degrader of the mutant p110α catalytic subunit of mutant PI3Kα. The molecule selectively depletes mutant p110α in cancer cells with active RTK (receptor tyrosine kinase) signaling and is in several ongoing or planned Ph. III trials for breast cancer. In October 2024, it received FDA approval for use in combination with palbociclib and fulvestrant to treat adults with endocrine-resistant, PIK3CA-mutated, HR+/HER2- breast cancer. This article explains how it works, how it was discovered, and why it matters.

BMS-986408 is an oral, dual DGK ⍺ and ζ inhibitor currently in a Ph. I/II trial in patients with solid tumors. The compound was identified stemming from a phenotypic screening approach, and subsequent target deconvolution revealed DGK to be the target. If approved, it would be a first-in-class intracellular checkpoint inhibitor of DGK. This is an excellent case study on how to overcome a DILI risk associated with BSEP inhibition, as well as how to improve solubility and PK properties of your compounds through the introduction of polarity, reduction of aromatic rings, and increase in f(sp3).