An MCL1 inhibitor, S63845, has antitumor activity in multiple hematologic malignancies in vivo.

  • Major finding: An MCL1 inhibitor, S63845, has antitumor activity in multiple hematologic malignancies in vivo.

  • Mechanism: S63845 promotes cell death via activation of the BAX/BAK-dependent mitochondrial apoptotic pathway.

  • Impact: MCL1 may be a druggable target that can be inhibited to induce apoptosis in multiple malignancies.


Myeloid cell leukemia 1 (MCL1) is a prosurvival protein that interacts with the BH3 domain of proapoptotic proteins to control the commitment to apoptosis. MCL1 is overexpressed in multiple malignancies, making it an attractive therapeutic target. However, no suitable drug-like inhibitors are available, and it is unclear if MCL1 targeting will be tolerable, because MCL1 is essential for the survival of multiple cell types. Kotschy, Szlavik, and colleagues discovered a small-molecule inhibitor of MCL1, S63845, that bound specifically to the BH3-binding groove of MCL1, similar to other BH3 mimetics. An MCL1-dependent multiple myeloma cell line exhibited much greater sensitivity to S63845 than to other BH3 mimetics, and S63845 induced BAX/BAK-dependent cell death through the mitochondrial apoptotic pathway. In total, 17 of 25 multiple myeloma cells lines were highly sensitive to S63845, 6 were moderately sensitive, and 2 were insensitive. Sensitivity was observed across molecular subtypes, including those harboring t(11;14) or t(4;14) chromosomal translocations or TP53 mutations. In vivo, S63845 was well tolerated and inhibited the growth of multiple myeloma xenografts in a dose-dependent manner. Further, S63845 sensitivity was observed in the majority of human lymphoma, chronic myeloid leukemia, and acute myeloid leukemia cell lines, but normal hematopoietic progenitor cells were insensitive. S63845 also had potent antitumor activity in c-MYC–driven mouse lymphoma and AML xenograft models, altogether indicating that S63845 has activity against a broad range of hematologic malignancies. Although most solid tumor–derived cell lines were resistant to S63845, sensitivity was observed in 3 of 20 non–small cell lung carcinoma, 3 of 9 breast cancer, and 3 of 12 melanoma cell lines. In these cells, the effects of S63845 were potentiated by inhibitors targeting oncogenic kinases. In addition to discovering a potent, selective MCL1 inhibitor, these results indicate that MCL1 inhibition is feasible, induces apoptosis, and has antitumor activity in diverse tumor types.

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 2016;538:477–82.