Selective Covalent Targeting of Anti‐Apoptotic BFL‐1 by a Sulfonium Tethered Peptide

Anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins were proven targets for human cancers. Targeting the BH3-binding pockets of these anti-apoptotic proteins could reactivate apoptosis in BCL-2-depedent cancers. BFL-1 is a BCL-2 family protein overexpressed in various chemoresistant cancers. A unique cysteine at the binding interface of the BH3 and BFL-1 was previously proven as an intriguing targeting site to irreversibly inhibit BFL-1 functions with stabilized cyclic peptide bearing a covalent warhead. Recently, we developed a sulfonium tethered peptide cyclization strategy to construct peptide ligands which could selectively and efficiently react with cysteine(s) of target proteins nearby the interacting interface. Utilizing this method, we constructed a BFL-1 peptide inhibitor B4-MC, which could selectively conjugate with BFL-1 both in vitro and in cell. B4-MC showed good cellular uptake, colocalized with BFL-1 on mitochondria, and showed obvious growth inhibition of BFL-1 over-expressed cancer cell lines.