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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use*
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Apoptosis / drug effects
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Cell Line, Tumor
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Female
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Humans
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Leukemia / drug therapy
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Leukemia / metabolism
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Leukemia / pathology
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Lymphoma / drug therapy
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Lymphoma / metabolism
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Lymphoma / pathology
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Male
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Mice
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Models, Biological*
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Models, Molecular
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Multiple Myeloma / drug therapy
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
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Myeloid Cell Leukemia Sequence 1 Protein / chemistry
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use*
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Thiophenes / administration & dosage
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Thiophenes / pharmacology*
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Thiophenes / therapeutic use*
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Xenograft Model Antitumor Assays
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / metabolism
Substances
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Antineoplastic Agents
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BAK1 protein, human
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Pyrimidines
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S63845
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Thiophenes
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein