Download MendeleyIn Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties.
Velter, I.A., Lento, W., Peschiulli, A., Reuillon, T.D., Ferrer, S., Orgaz-Gordillo, S., Buijnsters, P., De Boeck, B.C.A.G., Demin, S., Van Roosbroeck, Y., Jouffroy, M., Vos, A., Miller, B., Shaffer, P., Koo, S.J., Dominguez Blanco, M., McQueen, L., Altrocchi, C., Bueters, R., Vinken, P., Bekkers, M., Steyvers, H., Guttke, C., Walker, D., Bauser, M., Wilson, D.M., Philippar, U., Rombouts, F.J.R.(2025) J Med Chem 68: 16989-17029
- PubMed: 40825222
- DOI: https://doi.org/10.1021/acs.jmedchem.4c03166
- Primary Citation of Related Structures:
9PQ5, 9PQ6, 9PQ7 - PubMed Abstract:
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).
- Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Organizational Affiliation:
