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).