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.

NDI-101150 is an oral HPK1 inhibitor discovered by Nimbus Therapeutics and is currently in Ph. I/II clinical trial in advanced solid tumors. HPK1 is a compelling immuno-oncology target due to its critical role in regulating T-cells, B-cells, and dendritic cell-mediated immune responses. HPK1-deficient mice demonstrate enhanced anti-tumor T-cell responses and resistance to tumor growth. In this article, we detail the discovery of NDI-101150, as highlighted by Nimbus at the ACS Fall 2024 First-Time Disclosures session, interim results from the clinic, and more.

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!

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.

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.