title: Development of dimeric modulators for anti-apoptotic Bcl-2 proteins.
abstract: Bcl-2 family proteins can be classified into two subfamilies--anti-apoptotic members and pro-apoptotic members. Mechanistically, these two subfamilies can antagonize each other through heterodimerization while homodimerization has been proposed for each subfamily to carry out their corresponding anti-apoptotic or pro-apoptotic functions. To date, many small-molecule antagonists against anti-apoptotic Bcl-2 proteins have been developed, which are monomeric modulators. In this study, a series of BH3I-1 based dimeric modulators were developed with structure-activity relationship explored. Dimeric modulators compared to the monomeric antagonists have enhanced binding activity against anti-apoptotic Bcl-2 proteins. In addition, the acidic functional group was demonstrated to be critical for the binding interaction of the small-molecule antagonists with anti-apoptotic Bcl-2 proteins. Finally, the representative dimeric modulator revealed enhanced activity in inducing cytochrome c release from mitochondria compared to its monomeric counterpart. Taken together, dimerization of monomeric modulators is one practical approach to enhance the bioactivity of Bcl-2 antagonists.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota Minneapolis, MN 55455, USA.
authors.forename: Liangyou
authors.initials: L
authors.lastname: Wang
authors.forename: Fansen
authors.initials: F
authors.lastname: Kong
authors.forename: Candis L
authors.initials: CL
authors.lastname: Kokoski
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019281:Dimerization; D007700:Kinetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045162:Thiazolidinediones; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C503945:5-(4-bromobenzylidene)-alpha-isopropyl-4-oxo-2-thioxo-3-thazolidineacetic acid; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D045162:Thiazolidinediones; D051020:bcl-X Protein