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

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.

• Authors: 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 Blasko, Alan Robertson, Allan Surgenor, Pawel Dokurno, Ijen Chen, Natalia Matassova, Julia Smith, Christopher Pedder, Christopher Graham, Aurélie Studeny, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Gravé, David Segal, Chris D Riffkin, Giovanna Pomilio, Laura C A Galbraith, Brandon J Aubrey, Margs S Brennan, Marco J Herold, Catherine Chang, Ghislaine Guasconi, Nicolas Cauquil, Fabien Melchiore, Nolwen Guigal-Stephan, Brian Lockhart, Frédéric Colland, John A Hickman, Andrew W Roberts, David C S Huang, Andrew H Wei, Andreas Strasser, Guillaume Lessene, Olivier Geneste
• Journal: Nature (Nature) Vol. 538 Issue 7626 Pg. 477-482 (10 27 2016) ISSN: 1476-4687 [Electronic] England
• PMID: 27760111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BAK1 protein, human
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Pyrimidines
• S63845
• Thiophenes
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Female
• Humans
• Leukemia (drug therapy, metabolism, pathology)
• Lymphoma (drug therapy, metabolism, pathology)
• Male
• Mice
• Models, Biological
• Models, Molecular
• Multiple Myeloma (drug therapy, metabolism, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, chemistry, metabolism)
• Neoplasms (drug therapy, metabolism, pathology)
• Pyrimidines (administration & dosage, pharmacology, therapeutic use)
• Thiophenes (administration & dosage, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)
• bcl-2-Associated X Protein (metabolism)