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!

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.

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.

EOS-984 is an oral, potential first-in-class, highly selective ENT1 inhibitor from iTeos currently in clinical trials for advanced solid tumors. The drug, which was identified through SBDD and optimization of the vasodilator dilazep, targets the immunosuppressive effects of adenosine, which helps tumors evade immune detection. This is an excellent case study on the importance of understanding a molecule's bioactive conformation to reduce the entropy of binding and enhance potency.