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Publication Abstract from PubMed

Myeloid Cell Leukemia 1, or MCL-1, is an anti-apoptotic protein belonging to the BCL-2 family of proteins, which regulate the mitochondrial pathway of cellular apoptosis via binding of pro- and anti-apoptotic family members. Genetic amplification and overexpression of MCL-1 is one mechanism cancer cells utilize to avoid death and thus MCL-1 has emerged as an attractive target for cancer treatment. Herein, we describe our strategy and medicinal chemistry efforts to identify best-in-class MCL-1 inhibitors with high cytotoxic potency and improved biorelevant solubility while aiming to maximize therapeutic index versus on-target toxicity via IV dosing. These efforts led to the discovery of JNJ-78394355: a highly efficient anti-tumor agent, as demonstrated by the in vivo studies in human-xenograft mouse models of acute myeloid leukemia (AML) and multiple myeloma (MM).

In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties.,Velter IA, Lento W, Peschiulli A, Reuillon TD, Ferrer S, Orgaz-Gordillo S, Buijnsters P, De Boeck BCAG, Demin S, Van Roosbroeck Y, Jouffroy M, Vos A, Miller B, Shaffer P, Koo SJ, Dominguez Blanco M, McQueen L, Altrocchi C, Bueters R, Vinken P, Bekkers M, Steyvers H, Guttke C, Walker D, Bauser M, Wilson DM, Philippar U, Rombouts FJR J Med Chem. 2025 Aug 28;68(16):16989-17029. doi: 10.1021/acs.jmedchem.4c03166. , Epub 2025 Aug 18. PMID:40825222^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.