Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2011 May 12;54(9):3306-18. doi: 10.1021/jm101651b. Epub 2011 Apr 13.
We have synthesized and evaluated a series of nonpeptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultrapotent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC(50) from 1 to 3 nM in the MDA-MB-231 breast cancer cell line and are 100 times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations and hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts while causing no signs of toxicity in the animals.
我们合成并评价了一系列非肽类、双价 Smac 模拟物，作为凋亡抑制蛋白的拮抗剂和新型抗癌药物。所有这些双价 Smac 模拟物都以低纳摩尔亲和力结合全长 XIAP，并作为 XIAP 的超强拮抗剂发挥作用。虽然这些 Smac 模拟物与 cIAP1/2 具有相似的低纳摩尔亲和力，但它们在细胞中诱导 cIAP1/2 蛋白降解的效力相差 100 多倍。最有效的双价 Smac 模拟物在 MDA-MB-231 乳腺癌细胞系中以 1 至 3 nM 的 IC(50)抑制细胞生长，比最不有效的化合物强 100 倍。对几种代表性化合物的细胞内浓度的测定表明，这些双价 Smac 模拟物中的连接子显著影响它们的细胞内浓度，从而影响整体细胞活性。化合物 27 完全抑制 MDA-MB-231 异种移植瘤的生长，而在动物中没有毒性迹象。
