title: Bivalent Smac mimetics with a diazabicyclic core as highly potent antagonists of XIAP and cIAP1/2 and novel anticancer agents.
abstract: Nonpeptidic, bivalent Smac mimetics designed based upon monovalent Smac mimetics with a diazabicyclic core structure bind to XIAP, cIAP1, and cIAP2 with low to subnanomolar affinities and are highly effective in antagonizing XIAP in cell-free functional assays. They efficiently induce the degradation of cIAP1 and cIAP2 in cancer cells at concentrations as low as 1 nM, activate caspase-3 and -8, and cleave PARP at 3-10 nM. The most potent compounds in the series have IC(50) of 3-5 nM in inhibition of cell growth in both MDA-MB-231 and SK-OV-3 cell lines and are promising lead compounds for the development of a new class of cancer therapy.
authors.affiliation: Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, United States.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Peng
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Cai
authors.forename: Rong
authors.initials: R
authors.lastname: Shen
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Han
authors.initials: H
authors.lastname: Yi
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D057786:Peptidomimetics; C532637:SMAC peptide; D051636:X-Linked Inhibitor of Apoptosis Protein; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9