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

Harvey, Edward P.; Hauseman, Zachary J.; Cohen, Daniel T.; Rettenmaier, T. Justin; Lee, Susan; Huhn, Annissa J.; Wales, Thomas E.; Seo, Hyuk-Soo; Luccarelli, James; Newman, Catherine E.; Guerra, Rachel M.; Bird, Gregory H.; Dhe-Paganon, Sirano; Engen, John R.; Wells, James A.; Walensky, Loren D.

doi:10.1016/j.chembiol.2020.04.004

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

Journal Article · Mon Jun 01 00:00:00 EDT 2020 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2020.04.004· OSTI ID:1829847

Harvey, Edward P. ^[1]; Hauseman, Zachary J. ^[1]; Cohen, Daniel T. ^[1]; Rettenmaier, T. Justin ^[2]; Lee, Susan ^[1]; Huhn, Annissa J. ^[1]; Wales, Thomas E. ^[3]; Seo, Hyuk-Soo ^[4]; Luccarelli, James ^[1]; Newman, Catherine E. ^[1]; Guerra, Rachel M. ^[1]; Bird, Gregory H. ^[1]; Dhe-Paganon, Sirano ^[4]; Engen, John R. ^[3]; Wells, James A. ^[2]; Walensky, Loren D. ^[1]

Dana-Farber Cancer Inst., Boston, MA (United States). Dept. of Pediatric Oncology. Linde Program in Cancer Chemical Biology
Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology
Northeastern Univ., Boston, MA (United States). Dept. of Chemistry and Chemical Biology
Dana-Farber Cancer Inst., Boston, MA (United States). Dept. of Cancer Biology

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1829847

Journal Information:: Cell Chemical Biology, Vol. 27, Issue 6; ISSN 2451-9456

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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