Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer.

A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

制备了一系列二聚大环化合物，并对其作为凋亡蛋白抑制剂的拮抗剂进行了评估。活性最强的类似物11能以高亲和力与X连锁凋亡抑制蛋白（XIAP）和细胞凋亡抑制蛋白1（c-IAP）结合，诱导半胱天冬酶 - 3激活并最终引发细胞凋亡，在纳摩尔低浓度下即可抑制人黑色素瘤和结肠癌细胞系的生长。此外，在A875人黑色素瘤异种移植模型中，化合物11按每3天一次的给药方案，剂量低至2毫克/千克时就显示出显著的抗肿瘤活性。