AstraZeneca recently disclosed the structure and discovery journey of their oral small molecule PCSK9 inhibitor, AZD0780, during the ACS Fall 2024 First Time Disclosures session in Denver. Discover how the team identified a fragment hit targeting a previously unexplored pocket, verified its novel mechanism of action, and successfully advanced it into a clinical compound now in Ph. II trials for patients with dyslipidemia.

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.

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

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.

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.