Abstract
MCL-1 is an anti-apoptotic BCL-2 family protein that has emerged as a major pathogenic factor across a broad range of human cancers. Thus, pharmacologic inhibition of MCL-1 has been the focus of intensive drug development efforts. Like BCL-2, MCL-1 bears a C-terminal surface groove whose function is to bind and sequester the essential BH3 killer domains of pro-apoptotic BCL-2 family proteins, a mechanism harnessed by cancer cells to create formidable apoptotic blockades. Whereas drugging the BH3-binding groove has been successfully achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small molecule covalent modification of an interaction site that is distant from the BH3-binding groove. Biochemical and hydrogen-deuterium exchange mass spectrometry analyses revealed that both the BH3-binding capacity of MCL-1 and its functional suppression of BAX-mediated membrane poration is impaired by molecular engagement, a phenomenon recapitulated by mutagenic mimicry at the novel regulatory region. This allosteric mechanism for disrupting the anti-apoptotic, BH3-binding activity of MCL-1 could inform a new therapeutic strategy for disarming MCL-1 in cancer.
Citation Format: Susan Lee, Thomas E. Wales, Catherine Gallagher, Daniel T. Cohen, Silvia Escudero, James Luccarelli, Annissa J. Huhn, Nicole A. Cohen, Gregory H. Bird, John R. Engen, Loren D. Walensky. A novel allosteric mechanism for molecular inhibition of anti-apoptotic MCL-1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3553.
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