Design, Synthesis, and Evaluation of Potent, Nonpeptidic Mimetics of Second Mitochondria-Derived Activator of Caspases

• Published in: Journal of medicinal chemistry Vol. 52; no. 3; pp. 593 - 596
• Main Authors: Sun, Wei, Nikolovska-Coleska, Zaneta, Qin, Dongguang, Sun, Haiying, Yang, Chao-Yie, Bai, Longchuang, Qiu, Su, Wang, You, Ma, Dawei, Wang, Shaomeng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.02.2009; Amer Chemical Soc
• Subjects: Alanine - analogs & derivatives; Alanine - chemical synthesis; Alanine - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line, Tumor; Chemistry, Medicinal; General aspects; Humans; Inhibitor of Apoptosis Proteins - chemical synthesis; Inhibitor of Apoptosis Proteins - chemistry; Intracellular Signaling Peptides and Proteins - chemical synthesis; Life Sciences & Biomedicine; Medical sciences; Mitochondrial Proteins - chemical synthesis; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; X-Linked Inhibitor of Apoptosis Protein - metabolism; CANCER-CELLS; SMAC/DIABLO; STRUCTURAL BASIS; ALPHA-DEPENDENT APOPTOSIS; CONSTRAINED SMAC MIMETICS; XIAP; TARGETS; ANTAGONISTS; INHIBITOR; IAP PROTEINS; Human; Molecular rigidity; Peptidomimetic compound; Mimetic; Lactam; Non peptide compound; Steric hindrance; Molecular interaction; Naphthalene derivatives; In vitro; Second mitochondria derived activator of caspase protein; Biological fixation; Cell line; Structure activity relation; Mammary gland; Chemical synthesis; Tumor cell; Apoptosis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801101z

A series of new Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 10 binds to XIAP, cIAP-1, and cIAP-2 BIR3 proteins with K i of 3.9, 0.37, and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC50 of 8.9 nM.