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!

AbbVie’s ABBV-467 is a highly potent, selective MCL-1 (myeloid cell leukemia-1) inhibitor which entered the clinic in 2022 in a Ph. I trial in patients with advanced hematologic cancers. MCL-1 has had a rough time in the clinic with multiple trials being halted or terminated due to cardiac toxicity, which is suspected to be an on-target effect. AbbVie’s approach with ABBV-467 was to target a highly potent/short half-life compound which could induce rapid apoptosis and tumor regressions in a short exposure period before the onset of any adverse events. Is this the end for MCL-1?

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.

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.

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.