S63845

S63845 is a synthetic small-molecule inhibitor of MCL-1, an anti-apoptotic member of the BCL-2 protein family. It functions as a BH3 mimetic that binds selectively to MCL-1, inhibiting its interaction with pro-apoptotic proteins and enabling apoptosis in cells that depend on MCL-1 for survival.

In preclinical studies, S63845 demonstrated potent anti-tumor activity in a variety of cancer models, particularly hematologic malignancies such as multiple myeloma and acute myeloid leukemia, as well as some solid tumors with high MCL-1 dependence. The compound has been used both as a single agent and in combination with other therapies, including BCL-2 or BCL-XL inhibitors and standard chemotherapies, to overcome resistance.

Pharmacology and safety: S63845 shows high selectivity for MCL-1 over other BCL-2 family proteins, with activity observed in cultured cells and in vivo xenograft models. In animal studies, MCL-1 inhibition can cause toxic effects in tissues reliant on MCL-1, such as heart and liver, highlighting potential safety concerns for systemic targeting. There are no clinical approvals for S63845; it is used in basic and translational research.

Discovery and references: S63845 was described in a 2016 study by Kotschy and colleagues as a potent and selective MCL-1 inhibitor with strong pro-apoptotic activity. The compound has since become a widely used tool compound in the study of MCL-1–dependent cancer biology.