In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties

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).

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Journal
Journal of Medicinal Chemistry
Published
2025-08-18
DOI
https://doi.org/10.1021/acs.jmedchem.4c03166
Primary Topic
Synthesis of Indole Derivatives
Type
article
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article

In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties

Petra Vinken, Aldo Peschiulli, William Lento, Bradley S. Miller et al.
Journal of Medicinal Chemistry
Synthesis of Indole Derivatives
article

In Pursuit of Best-in-Class MCL-1 Inhibitors: Discovery of Highly Potent 1,4-Indoyl Macrocycles with Favorable Physicochemical Properties

Petra Vinken, Aldo Peschiulli, William Lento, Bradley S. Miller, Sofía Ferrer, Ulrike Philippar, Lisa McQueen, David M. Wilson, Cristina Altrocchi, Frederik Rombouts, David Walker, Samuël Demin, P.L. Shaffer, Peter Buijnsters, Matthieu Jouffroy, Christina Guttke, Mariette Bekkers, Helena Steyvers, Maria Dominguez Blanco, Tristan Reuillon, Ingrid Velter, Ruud Bueters, Marcus Bauser, Yves Van Roosbroeck, Ann Vos, Sergio Orgaz‐Gordillo, Seong Joo Koo, Benoît C. A. G. De Boeck
article en

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).

Journal of Medicinal ChemistryVol. 68(16)
Janssen (Belgium) (BE), Institute of Process Engineering (CN), Janssen (United States) (US)
Zero hunger
Openalex Percentile: Top 84%
Synthesis of Indole Derivatives
DOISourceOpenAlex
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