title: Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists.
abstract: Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA. Electronic address: kyoung.kim@bms.com.
authors.forename: Kyoung Soon
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Perez
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Stang
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Shana
authors.initials: S
authors.lastname: Posy
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Chaudhry
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.affiliation: Bristol-Myers Squibb Research & Development, PO Box 4000, Princeton, NJ 08543, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Talbott
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D055808:Drug Discovery; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D044005:Tetrahydroisoquinolines
keywords: A875 melanoma; Bivalent; IAP; Terahydroisoquinoline