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.

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.

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

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.

HiberCell recently disclosed the discovery of HC-7366, a potential first-in-class, intentionally discovered, orally bioavailable, potent, selective, small-molecule kinase activator of GCN2. HC-7366 has now progressed to Ph. I trials to treat ccRCC and AML. This case study is a fantastic example of how to mitigate CYP3A4 inhibition and improve oral bioavailability via judicious choice of salt formulation.