The dysregulation of the anti-apoptotic Bcl-2 proteins, particularly Bcl-2, Bcl-x<sub>L</sub>, and Mcl-1, leads to the evasion of apoptosis, which is a hallmark of cancer. In addition to its direct role in promoting tumor growth in a variety of cancers that include acute myeloid leukemia and multiple myeloma, the over-expression of Mcl-1 has been associated with resistance to current chemotherapies. Mcl-1’s immortalizing role is manifested through the sequestration of the Bcl-2 pro-apoptotic proteins, such as Bim and Noxa, through their α-helical BH3 domains. This occurs through a hydrophobic groove comprising four binding pockets termed p1 through p4 that recognize four conserved hydrophobic residues projected from one face of the BH3 α-helix, along with a conserved arginine, R263 (Mcl-1) that engages a conserved aspartate on the opposing face of the helix. Recently, we reported on <i>N</i>-substituted 1-hydroxy-4-sulfamoyl-2-naphthoic acids as selective, nanomolar inhibitors of Mcl-1. Molecular modeling suggested that only the p2 pocket is engaged by the inhibitors. It is hypothesized that even greater potencies will be realized through the replacement of the carboxylic acid with various acylsulfonamides whose introduced moieties will extend into the p4 pocket. Moreover, this bioisosteric replacement may promote cell penetration and reduce serum binding that is typical of lipophilic inhibitors bearing acidic groups. Our efforts toward this endeavor will be presented along with comprehensive structure acitivity relationship studies.

Substituted acylsulfonamides as surrogates of a terminal carboxylic acid: More effective small-molecule blockade of the Mcl-1 oncoprotein

253rd National Meeting (2017)

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