一种有效的双价 Smac 模拟物（SM-1200）可使小鼠迅速、完全和持久地肿瘤消退。
A potent bivalent Smac mimetic (SM-1200) achieving rapid, complete, and durable tumor regression in mice.
机构信息
Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
出版信息
J Med Chem. 2013 May 23;56(10):3969-79. doi: 10.1021/jm400216d. Epub 2013 May 7.
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.
摘要
我们设计、合成并评估了一系列基于我们之前报道的双价 Smac 模拟物的新化合物。这导致了化合物 12（SM-1200）的鉴定，它分别与 XIAP、cIAP1 和 cIAP2 的 Ki 值为 0.5、3.7 和 5.4 nM，在 MDA-MB-231 乳腺癌和 SK-OV-3 卵巢癌细胞系中的 IC50 值分别为 11.0 和 28.2 nM。与我们之前报道的双价 Smac 模拟物相比，化合物 12 的药代动力学特性有了很大的改善，并且在 MDA-MB-231 异种移植模型中诱导快速和持久的肿瘤消退方面非常有效。这些数据表明，化合物 12 是一种很有前途的 Smac 模拟物，值得作为临床开发的潜在候选药物进行广泛评估。
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