The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Ana Leticia Maragno, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Gemma L. Kelly, Jia Nan Gong, Donia M. Moujalled, Alain Bruno, Márton Csekei, Attila Paczal, Zoltán B. Szabo, Szabolcs Sipos, Gábor Radics, Agnes Proszenyak, Balázs Balint, Levente Ondi, Gábor BlaskoGiovanna Pomilio, Andrew H. Wei

Research output: Contribution to journalArticleResearchpeer-review

398 Citations (Scopus)

Abstract

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Original languageEnglish
Pages (from-to)477-482
Number of pages6
JournalNature
Volume538
Issue number7626
DOIs
Publication statusPublished - 2016

Cite this

Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., Le Toumelin-Braizat, G., Chanrion, M., Kelly, G. L., Gong, J. N., Moujalled, D. M., Bruno, A., Csekei, M., Paczal, A., Szabo, Z. B., Sipos, S., Radics, G., Proszenyak, A., Balint, B., Ondi, L., ... Wei, A. H. (2016). The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature, 538(7626), 477-482. https://doi.org/10.1038/nature19830