title: Design, synthesis, and evaluation of a potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase (Smac) mimetic.
abstract: A potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase mimetic (SM-131, 2) has been designed, synthesized, and evaluated. Compound 2 binds to X-linked inhibitors of apoptosis proteins (XIAP) with a Ki of 61 nM in a competitive binding assay and directly antagonizes the XIAP inhibition of caspase-9 activity in a cell-free functional assay. Compound 2 achieves an IC50 of 100 nM in inhibition of cell growth and effectively induces cell death in the MDA-MB-231 human breast cancer cell line.
authors.affiliation: Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Su
authors.initials: S
authors.lastname: Qiu
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meagher
authors.forename: Jeanne
authors.initials: J
authors.lastname: Stuckey
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C516690:6-(2-methylaminobutyrylamino)-5-oxooctahydropyrrolo(1,2-a)azepine-3-carboxylic acid; D001381:Azepines; D061945:Caspase Inhibitors; D006571:Heterocyclic Compounds; D051034:Inhibitor of Apoptosis Proteins; D011759:Pyrrolidines; D051636:X-Linked Inhibitor of Apoptosis Protein; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3; D053453:Caspase 9