title: A potent bivalent Smac mimetic (SM-1200) achieving rapid, complete, and durable tumor regression in mice.
abstract: We have designed, synthesized, and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1, and cIAP2 with Ki values of 0.5, 3.7, and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.
authors: Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Rong
authors: R
authors: Sheng
authors: Haiying
authors: H
authors: Sun
authors: Liu
authors: L
authors: Liu
authors: Jianfeng
authors: J
authors: Lu
authors: Donna
authors: D
authors: McEachern
authors: Guanfeng
authors: G
authors: Wang
authors: Jianfeng
authors: J
authors: Wen
authors: Ping
authors: P
authors: Min
authors: Zhenyun
authors: Z
authors: Du
authors: Huirong
authors: H
authors: Lu
authors: Sanmao
authors: S
authors: Kang
authors: Ming
authors: M
authors: Guo
authors: Dajun
authors: D
authors: Yang
authors: Shaomeng
authors: S
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins; D019540:Area Under Curve; D001392:Azocines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007202:Indicators and Reagents; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000494:pharmacology; D010655:Phenylenediamines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001392:Azocines; D002352:Carrier Proteins; C489013:DIABLO protein, rat; D007202:Indicators and Reagents; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; C582343:N3,N3'-(-cyclohexane-1,4-diyl)bis(N8-benzhydryl-5-(2-(methylamino)propanamido)-6-oxooctahydropyrrolo(1,2-a)(1,5)diazocine-3,8(4H)-dicarboxamide); D010655:Phenylenediamines; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3; D053453:Caspase 9
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