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.

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!

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.

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.

As the “Guardian of the Genome,” the tumor suppressor transcription factor p53 has been a much sought-after target in oncology, with over 50% of malignancies showing mutations in p53. The p53(Y220C) mutant has been of particular interest as it creates a pocket which small molecule stabilizers are able to bind to and restore p53 function. PMV Pharma is the first to enter the clinic with their p53(Y220C) stabilizer rezatapopt, which was optimized from a hybrid of known binders and which is showing real promise against a swath of solid tumors.