title: Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1.
abstract: A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-X(L), and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-X(L), and Bcl-w, and a set of inhibitors with varied selectivity to Bcl-2, Bcl-X(L), and Bcl-w proteins have been identified. Molecular modeling of the interaction of the BHI-1 based analogues with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-X(L), and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for anti-apoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-X(L), and Bcl-w by targeting the non-conserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling-aided rational development of BHI-1 based selective inhibitor for anti-apoptotic Bcl-2 proteins is underway.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, 8-101 WDH 308 Harvard ST SE, Minneapolis, MN 55455, USA. xingx009@umn.edu
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
authors.forename: Liangyou
authors.initials: L
authors.lastname: Wang
authors.forename: XiaoHu
authors.initials: X
authors.lastname: Tang
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D005454:Fluorescence Polarization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins