Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.

Cell chemical biology 2020 Jun 18

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The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Edward P Harvey, Zachary J Hauseman, Daniel T Cohen, T Justin Rettenmaier, Susan Lee, Annissa J Huhn, Thomas E Wales, Hyuk-Soo Seo, James Luccarelli, Catherine E Newman, Rachel M Guerra, Gregory H Bird, Sirano Dhe-Paganon, John R Engen, James A Wells, Loren D Walensky. Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering. Cell chemical biology. 2020 Jun 18;27(6):647-656.e6