A Potent and Orally Active Antagonist (SM-406/AT-406) of Multiple Inhibitor of Apoptosis Proteins (IAPs) in Clinical Development for Cancer Treatment

We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K i of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effec...

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Published in	Journal of medicinal chemistry Vol. 54; no. 8; pp. 2714 - 2726
Main Authors	Cai, Qian, Sun, Haiying, Peng, Yuefeng, Lu, Jianfeng, Nikolovska-Coleska, Zaneta, McEachern, Donna, Liu, Liu, Qiu, Su, Yang, Chao-Yie, Miller, Rebecca, Yi, Han, Zhang, Tao, Sun, Duxin, Kang, Sanmao, Guo, Ming, Leopold, Lance, Yang, Dajun, Wang, Shaomeng
Format	Journal Article
Language	English
Published	WASHINGTON American Chemical Society 28.04.2011 Amer Chemical Soc
Subjects	Administration, Oral Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects Area Under Curve Azocines - pharmacokinetics Azocines - pharmacology Azocines - therapeutic use Benzhydryl Compounds - pharmacokinetics Benzhydryl Compounds - pharmacology Benzhydryl Compounds - therapeutic use Biological Availability Cell Line, Tumor Chemistry, Medicinal Humans Inhibitor of Apoptosis Proteins - antagonists & inhibitors Life Sciences & Biomedicine Models, Molecular Neoplasms - drug therapy Pharmacology & Pharmacy Science & Technology SMALL-MOLECULE MIMETICS X-LINKED INHIBITOR MITOCHONDRIA-DERIVED ACTIVATOR XIAP BIR3 DOMAIN STRUCTURAL BASIS ALPHA-DEPENDENT APOPTOSIS CASPASE INHIBITION CONSTRAINED SMAC MIMETICS NF-KAPPA-B STRUCTURE-BASED DESIGN
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Abstract	We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K i of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.
AbstractList	We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K(i) of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K(i) of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer. We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K(i) of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer. We report the discovery and characterization of SM-406 (compound 2 ), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with K i values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.
Author	Wang, Shaomeng Yi, Han Cai, Qian Sun, Haiying Yang, Chao-Yie Liu, Liu Peng, Yuefeng Kang, Sanmao McEachern, Donna Leopold, Lance Sun, Duxin Lu, Jianfeng Qiu, Su Miller, Rebecca Guo, Ming Yang, Dajun Nikolovska-Coleska, Zaneta Zhang, Tao
AuthorAffiliation	Ascenta Therapeutics University of Michigan
AuthorAffiliation_xml	– name: University of Michigan – name: Ascenta Therapeutics – name: Ascenta Therapeutics, 101 Lindenwood Drive, Malvern, PA 19355, USA – name: Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA – name: Δ Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
Author_xml	– sequence: 1 givenname: Qian surname: Cai fullname: Cai, Qian – sequence: 2 givenname: Haiying surname: Sun fullname: Sun, Haiying – sequence: 3 givenname: Yuefeng surname: Peng fullname: Peng, Yuefeng – sequence: 4 givenname: Jianfeng surname: Lu fullname: Lu, Jianfeng – sequence: 5 givenname: Zaneta surname: Nikolovska-Coleska fullname: Nikolovska-Coleska, Zaneta – sequence: 6 givenname: Donna surname: McEachern fullname: McEachern, Donna – sequence: 7 givenname: Liu surname: Liu fullname: Liu, Liu – sequence: 8 givenname: Su surname: Qiu fullname: Qiu, Su – sequence: 9 givenname: Chao-Yie surname: Yang fullname: Yang, Chao-Yie – sequence: 10 givenname: Rebecca surname: Miller fullname: Miller, Rebecca – sequence: 11 givenname: Han surname: Yi fullname: Yi, Han – sequence: 12 givenname: Tao surname: Zhang fullname: Zhang, Tao – sequence: 13 givenname: Duxin surname: Sun fullname: Sun, Duxin – sequence: 14 givenname: Sanmao surname: Kang fullname: Kang, Sanmao – sequence: 15 givenname: Ming surname: Guo fullname: Guo, Ming – sequence: 16 givenname: Lance surname: Leopold fullname: Leopold, Lance – sequence: 17 givenname: Dajun surname: Yang fullname: Yang, Dajun – sequence: 18 givenname: Shaomeng surname: Wang fullname: Wang, Shaomeng email: shaomeng@umich.edu
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/21443232$$D View this record in MEDLINE/PubMed
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Keywords	SMALL-MOLECULE MIMETICS X-LINKED INHIBITOR MITOCHONDRIA-DERIVED ACTIVATOR XIAP BIR3 DOMAIN STRUCTURAL BASIS ALPHA-DEPENDENT APOPTOSIS CASPASE INHIBITION CONSTRAINED SMAC MIMETICS NF-KAPPA-B STRUCTURE-BASED DESIGN
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Notes	NIH RePORTER ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally. Present address: For Qian Cai: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510663, China For Yuefeng Peng: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892, USA.
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PublicationTitle	Journal of medicinal chemistry
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PublicationYear	2011
Publisher	American Chemical Society Amer Chemical Soc
Publisher_xml	– name: American Chemical Society – name: Amer Chemical Soc
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Snippet	We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of... We report the discovery and characterization of SM-406 (compound 2 ), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of...
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SubjectTerms	Administration, Oral Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects Area Under Curve Azocines - pharmacokinetics Azocines - pharmacology Azocines - therapeutic use Benzhydryl Compounds - pharmacokinetics Benzhydryl Compounds - pharmacology Benzhydryl Compounds - therapeutic use Biological Availability Cell Line, Tumor Chemistry, Medicinal Humans Inhibitor of Apoptosis Proteins - antagonists & inhibitors Life Sciences & Biomedicine Models, Molecular Neoplasms - drug therapy Pharmacology & Pharmacy Science & Technology
Title	A Potent and Orally Active Antagonist (SM-406/AT-406) of Multiple Inhibitor of Apoptosis Proteins (IAPs) in Clinical Development for Cancer Treatment
URI	http://dx.doi.org/10.1021/jm101505d http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestApp=WOS&DestLinkType=FullRecord&UT=000289697800012 https://www.ncbi.nlm.nih.gov/pubmed/21443232 https://www.proquest.com/docview/863430349 https://pubmed.ncbi.nlm.nih.gov/PMC3520070
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