title: Design, synthesis and evaluation of monovalent Smac mimetics that bind to the BIR2 domain of the anti-apoptotic protein XIAP.
abstract: We report the systematic rational design and synthesis of new monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Characterization of compounds in vitro (including 9i; ML101) led to the determination of key structural requirements for BIR2 binding affinity. Compounds 9h and 9j sensitized TRAIL-resistant breast cancer cells to apoptotic cell death, highlighting the value of these probe compounds as tools to investigate the biology of XIAP.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Marcos
authors.initials: M
authors.lastname: González-López
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: Darren
authors.initials: D
authors.lastname: Finlay
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Santhi Reddy
authors.initials: SR
authors.lastname: Ganji
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Peter
authors.initials: P
authors.lastname: Teriete
authors.forename: Peter D
authors.initials: PD
authors.lastname: Mace
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Riedl
authors.forename: Kristiina
authors.initials: K
authors.lastname: Vuori
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry*; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein