title: Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors.
abstract: The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: alexander.hird@astrazeneca.com.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Hird
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Aquila
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Kamhi
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Omer
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Laing
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Jamal C
authors.initials: JC
authors.lastname: Saeh
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Sha
authors.affiliation: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D051034:Inhibitor of Apoptosis Proteins
keywords: Inhibitors of Apoptosis Proteins; Ring-closing metathesis; Smac; Structure-based drug design; XIAP; cIAP