Journal Article

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

Studeny, Aurélie, Wei, Andrew H., Pedder, Christopher, Smith, Julia, Girard, Anne-Marie, Blasko, Gábor, Lockhart, Brian, Roberts, Andrew W., Melchiore, Fabien, Surgenor, Allan, Riffkin, Chris D., Ondi, Levente, Murray, James, Herold, Marco J., Segal, David, Galbraith, Laura C. A., Aubrey, Brandon J., Kelly, Gemma L., Maragno, Ana Leticia, Sipos, Szabolcs, Paczal, Attila, Proszenyak, Agnes, Kotschy, András, Szlavik, Zoltán, Guasconi, Ghislaine, Csekei, Márton, Dokurno, Pawel, Strasser, Andreas, Gong, Jia-Nan, Chen, Ijen, Robertson, Alan, Radics, Gábor, Brennan, Margs S., Szabo, Zoltán B., Graham, Christopher, Bruno, Alain, Matassova, Natalia, Lessene, Guillaume, Cauquil, Nicolas, Pomilio, Giovanna, Lysiak-Auvity, Gaëlle, Geneste, Olivier, Gravé, Fabienne, Moujalled, Donia M., Balint, Balázs, Guigal-Stephan, Nolwen, Hickman, John A., Chanrion, Maïa, Davidson, James, Le Toumelin-Braizat, Gaëtane, Huang, David C. S., Colland, Frédéric, Chang, Catherine

2016

Overview

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. S63845 specifically inhibits MCL1 and induces tumour cell death in vitro and in vivo in diverse cancer-derived cell lines with an acceptable safety margin. MCL1 protein as a possible anti-cancer target These authors report the discovery and characterization of a novel inhibitor of the anti-apoptotic pro-survival protein MCL1, which is expressed by multiple tumour types. The compound, termed S63845, activates the BAX/BAK-dependent mitochondrial apoptotic pathway and shows efficacy in several solid tumour models, suggesting that inhibition of MCL1 could be a viable anti-cancer strategy, alone or in combination with other anti-cancer drugs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1059 / 692/308/153 / Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis / Apoptosis - drug effects / bcl-2 Homologous Antagonist-Killer Protein - metabolism / bcl-2-Associated X Protein - metabolism / Cancer / Cell Line, Tumor / Crystal structure / Cytotoxicity / Drug dosages / Female / Health aspects / Humanities and Social Sciences / Humans / Kinases / Leukemia / Leukemia - drug therapy / Leukemia - metabolism / Leukemia - pathology / Lymphoma / Lymphoma - drug therapy / Lymphoma - metabolism / Lymphoma - pathology / Male / Metastasis / Mice / Models, Biological / Models, Molecular / multidisciplinary / Multiple myeloma / Multiple Myeloma - drug therapy / Multiple Myeloma - metabolism / Multiple Myeloma - pathology / Myelocytic leukemia / Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors / Myeloid Cell Leukemia Sequence 1 Protein - chemistry / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Nonlymphoid leukemia / Observations / Physiological aspects / Proteins / Pyrimidines - administration & dosage / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Science / Studies / Thiophenes - administration & dosage / Thiophenes - pharmacology / Thiophenes - therapeutic use / Tumors / Xenograft Model Antitumor Assays