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?

Novartis’ HRO761 is an oral allosteric WRN helicase inhibitor, aimed at treating MSI-high and dMMR tumors. This article details the discovery of HRO761 and highlights the importance of selecting appropriate assays during early HTS as well as transferable medicinal chemistry strategies to optimize permeability and solubility through the modulation of LipE, neutral TPSA, chameleonicity, and non-classical zwitterions. It also explores the X-ray structure of HRO761 bound to WRN, how it differentiates from Vividion's VVD-214, its preclinical activity, clinical status, chemical synthesis, and more!

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor from Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.

BMS-986408 is an oral, dual DGK ⍺ and ζ inhibitor currently in a Ph. I/II trial in patients with solid tumors. The compound was identified stemming from a phenotypic screening approach, and subsequent target deconvolution revealed DGK to be the target. If approved, it would be a first-in-class intracellular checkpoint inhibitor of DGK. This is an excellent case study on how to overcome a DILI risk associated with BSEP inhibition, as well as how to improve solubility and PK properties of your compounds through the introduction of polarity, reduction of aromatic rings, and increase in f(sp3).

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.