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).