Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.
Department of Respiratory and Critical Care Medicine, West China Hospital , Sichuan University , Chengdu , Sichuan 610041 , China.
ACS Chem Biol. 2019 Dec 20;14(12):2810-2821. doi: 10.1021/acschembio.9b00696. Epub 2019 Nov 25.
Because of its multifaceted role in cellular functions, tubulin is a validated and productive drug target for cancer therapy. While many tubulin inhibitors demonstrate clinical efficacy, they are often limited by the development of multidrug resistance. Therefore, implementation of tubulin inhibitors that can overcome resistance could provide significant therapeutic benefits. To optimize our previously reported tubulin inhibitor, , we designed and synthesized two new analogues, and , based on the crystal structure of in complex with tubulin protein. and achieved enhanced binding at the colchicine site in tubulin and also showed improved metabolic stability and antiproliferative potency . Functional studies confirmed that and inhibit tubulin polymerization, arrest cells in the G/M phase of the cell cycle, interfere with cancer cell migration and proliferation, and enhance apoptotic cascades. When evaluated , exhibited antitumor and vascular disrupting action against paclitaxel-resistant mouse xenograft models, strongly suggesting the potential of this scaffold to overcome multidrug resistance for cancer therapy.
由于其在细胞功能中的多方面作用，微管蛋白已成为癌症治疗中一种经过验证且富有成效的药物靶点。虽然许多微管蛋白抑制剂具有临床疗效，但它们往往受到多药耐药性的发展的限制。因此，实施能够克服耐药性的微管蛋白抑制剂可能会带来显著的治疗益处。为了优化我们之前报道的微管蛋白抑制剂 ，我们基于 与微管蛋白结合的晶体结构，设计并合成了两种新的类似物 和 。 和 在微管蛋白的秋水仙碱结合部位实现了增强的结合，并且还表现出改善的代谢稳定性和抗增殖效力。功能研究证实， 和 抑制微管蛋白聚合，将细胞阻滞在细胞周期的 G/M 期，干扰癌细胞迁移和增殖，并增强凋亡级联。当进行评估时， 对紫杉醇耐药的小鼠异种移植模型表现出抗肿瘤和血管破坏作用，强烈表明该支架具有克服癌症治疗多药耐药性的潜力。
