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The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
András Kotschy1, Zoltán Szlavik1, James Murray2
1Servier Research Institute of Medicinal Chemistry, Budapest 1031, Hungary.
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.
Insights
A novel small molecule, S63845, effectively targets the pro-survival protein myeloid cell leukemia 1 (MCL1) in various cancers. This breakthrough offers a new therapeutic strategy for treating multiple myeloma, leukemia, lymphoma, and solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Tumor growth relies on evading apoptosis.
- Overexpression of myeloid cell leukemia 1 (MCL1), a pro-survival protein, is common in many cancers.
- Developing clinically viable small molecules targeting MCL1 has been difficult.
Purpose of the Study:
- To introduce S63845, a novel small molecule inhibitor of MCL1.
- To investigate the anti-cancer efficacy of S63845 in preclinical models.
Main Methods:
- Characterization of S63845 binding affinity to MCL1's BH3-binding groove.
- Assessment of S63845's ability to induce apoptosis in MCL1-dependent cancer cells.
- Evaluation of S63845's anti-tumor activity in vivo and in combination therapies.
Main Results:
- S63845 binds MCL1 with high affinity, inhibiting its pro-survival function.
- S63845 effectively kills MCL1-dependent cancer cells (multiple myeloma, leukemia, lymphoma) via the BAX/BAK pathway.
- S63845 demonstrates potent in vivo anti-tumor activity with a good safety profile and efficacy in combination treatments.
Conclusions:
- MCL1 is a validated therapeutic target for a broad spectrum of cancers.
- S63845 represents a promising new drug candidate for MCL1-targeted cancer therapy.
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