Potent, Orally Bioavailable Diazabicyclic Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases
A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K i values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional...
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| Published in | Journal of medicinal chemistry Vol. 51; no. 24; pp. 8158 - 8162 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
25.12.2008
Amer Chemical Soc |
| Subjects | |
| Online Access | Get full text |
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| Abstract | A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K i values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability. |
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| AbstractList | A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized and evaluated. The most potent compound (
6
) binds to XIAP, cIAP-1 and cIAP-2 with K
i
values of 8.4, 1.5 and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC
50
value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line and has a good oral bioavailability. A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K i values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability. A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability. A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIA-P-2 with K-i values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC50 value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability. A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability. |
| Author | Wang, Shaomeng Yi, Han Cai, Qian Sun, Haiying Yang, Chao-Yie Lu, Jianfeng Qiu, Su Peng, Yuefeng Kang, Sanmao Yang, Dajun Nikolovska-Coleska, Zaneta |
| AuthorAffiliation | Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Ascenta Therapeutics, Inc. 101 Lindenwood Drive, Suite 405, Malvern, PA 19355, USA |
| AuthorAffiliation_xml | – name: Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA; Ascenta Therapeutics, Inc. 101 Lindenwood Drive, Suite 405, Malvern, PA 19355, USA |
| Author_xml | – sequence: 1 givenname: Yuefeng surname: Peng fullname: Peng, Yuefeng – sequence: 2 givenname: Haiying surname: Sun fullname: Sun, Haiying – sequence: 3 givenname: Zaneta surname: Nikolovska-Coleska fullname: Nikolovska-Coleska, Zaneta – sequence: 4 givenname: Su surname: Qiu fullname: Qiu, Su – sequence: 5 givenname: Chao-Yie surname: Yang fullname: Yang, Chao-Yie – sequence: 6 givenname: Jianfeng surname: Lu fullname: Lu, Jianfeng – sequence: 7 givenname: Qian surname: Cai fullname: Cai, Qian – sequence: 8 givenname: Han surname: Yi fullname: Yi, Han – sequence: 9 givenname: Sanmao surname: Kang fullname: Kang, Sanmao – sequence: 10 givenname: Dajun surname: Yang fullname: Yang, Dajun – sequence: 11 givenname: Shaomeng surname: Wang fullname: Wang, Shaomeng email: shaomeng@umich.edu |
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| Keywords | CANCER-CELLS TARGET SMAC/DIABLO XIAP BIR3 DOMAIN STRUCTURAL BASIS ALPHA-DEPENDENT APOPTOSIS ANTAGONISTS BINDING IAP PROTEINS STRUCTURE-BASED DESIGN Human Rat Mimetic Rodentia Lactam Oral administration Bioavailability In vitro Second mitochondria derived activator of caspase protein Biological activity Vertebrata Mammalia Cell line Apoptosis inhibitory protein Animal Mammary gland Small molecule Pharmacokinetics Chemical synthesis Tumor cell Apoptosis |
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| Snippet | A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6)... A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized and evaluated. The most potent compound ( 6... |
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| SubjectTerms | Administration, Oral Animals Antineoplastic agents Baculoviral IAP Repeat-Containing 3 Protein Biological and medical sciences Caspase Inhibitors Cell Line, Tumor Cell Proliferation - drug effects Chemistry, Medicinal Chemistry, Pharmaceutical - methods Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology General aspects Humans Inhibitor of Apoptosis Proteins - chemistry Inhibitory Concentration 50 Life Sciences & Biomedicine Medical sciences Mitochondria - enzymology Mitochondria - metabolism Pharmacology & Pharmacy Pharmacology. Drug treatments Rats Science & Technology Ubiquitin-Protein Ligases X-Linked Inhibitor of Apoptosis Protein - chemistry |
| Title | Potent, Orally Bioavailable Diazabicyclic Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases |
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