Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists
| Autor: | David K. Williams, Charu Chaudhry, Robert M. Borzilleri, Liping Zhang, Randy Talbott, Kyoung S. Kim, Erik M. Stang, Ming Lei, Heidi L. Perez, Shana L. Posy, Stuart Emanuel |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Protein subunit Clinical Biochemistry Pharmaceutical Science Mice Nude Antineoplastic Agents Apoptosis Pharmacology Biochemistry Bivalent (genetics) Inhibitor of Apoptosis Proteins chemistry.chemical_compound Mice In vivo Tetrahydroisoquinolines Drug Discovery Tumor Cells Cultured Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Benzamide Molecular Biology Melanoma Mice Inbred BALB C Binding Sites Tetrahydroisoquinoline Organic Chemistry Xenograft Model Antitumor Assays Pancreatic Neoplasms chemistry Cell culture Molecular Medicine Female Linker |
| Zdroj: | Bioorganicmedicinal chemistry letters. 24(21) |
| ISSN: | 1464-3405 |
| Popis: | 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 1 mg/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. |
| Databáze: | OpenAIRE |
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