6vo4

Publication Abstract from PubMed

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.

Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.,Harvey EP, Hauseman ZJ, Cohen DT, Rettenmaier TJ, Lee S, Huhn AJ, Wales TE, Seo HS, Luccarelli J, Newman CE, Guerra RM, Bird GH, Dhe-Paganon S, Engen JR, Wells JA, Walensky LD Cell Chem Biol. 2020 Jun 18;27(6):647-656.e6. doi:, 10.1016/j.chembiol.2020.04.004. Epub 2020 May 14. PMID:32413285^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.