Kymera’s KT-413 is a CRBN-based dual-mechanism degrader that degrades both IRAK4 and the transcription factors IKZF1/3, acting as an IMiD, with promising clinical activity for the treatment of ABC-like subtype of DLBCL. This fascinating case study demonstrates how a dual-mechanism degrader of IKZF1/3 and IRAK4 can be designed to maximize NF-κB inhibition while simultaneously upregulating the Type I interferon response. This approach restores the apoptotic response and enables oncogene-mediated cell death, resulting in a robust antiproliferative and pro-apoptotic effect in MYD88 mutants.

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.

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.

BMS-986397 is a potential first-in-class CRBN-based selective CK1α molecular glue degrader. CK1α promotes tumor growth by enhancing MDM2 and MDMX degradation of the tumor suppressor p53. Since AML has a low TP53 mutation rate, activating the p53 pathway is a promising approach; however, p53 activators have faced challenges due to hematological toxicities. Targeting CK1α degradation offers an alternative approach. The BMS team sought to develop a CELMoD® for CK1α degradation. This article outlines the discovery of BMS-986397, as presented at the ACS Fall 2024 meeting in Denver, CO.

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.