X-ray Crystal Structure Guided Discovery and Antitumor Efficacy of Dihydroquinoxalinone as Potent Tubulin Polymerization Inhibitors.,ACS Chemical Biology

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X-ray Crystal Structure Guided Discovery and Antitumor Efficacy of Dihydroquinoxalinone as Potent Tubulin Polymerization Inhibitors.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-11-25 , DOI: 10.1021/acschembio.9b00696
Kinsie E Arnst ₁ , Souvik Banerjee ₁ , Yuxi Wang ₂ , Hao Chen ₁ , Yong Li ₃ , Lei Yang ₃ , Weimin Li ₂ , Duane D Miller ₁ , Wei Li ₁

Affiliation

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, 4a, we designed and synthesized two new analogues, SB202 and SB204, based on the crystal structure of 4a in complex with tubulin protein. SB202 and SB204 achieved enhanced binding at the colchicine site in tubulin and also showed improved metabolic stability and antiproliferative potency in vitro. Functional studies confirmed that SB202 and SB204 inhibit tubulin polymerization, arrest cells in the G2/M phase of the cell cycle, interfere with cancer cell migration and proliferation, and enhance apoptotic cascades. When evaluated in vivo, SB202 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.

中文翻译：

X射线晶体结构指导二氢喹喔啉酮作为有效的微管蛋白聚合抑制剂的发现和抗肿瘤功效。

由于微管蛋白在细胞功能中的多方面作用，因此它已成为癌症治疗中经过验证的生产性药物靶标。尽管许多微管蛋白抑制剂显示出临床功效，但它们通常受到多药耐药性发展的限制。因此，实施可克服耐药性的微管蛋白抑制剂可提供重大的治疗益处。为了优化我们先前报道的微管蛋白抑制剂4a，我们基于4a与微管蛋白蛋白复合的晶体结构，设计并合成了两个新的类似物SB202和SB204。SB202和SB204在微管蛋白中的秋水仙碱位点实现了增强的结合，并且在体外还表现出改善的代谢稳定性和抗增殖能力。功能研究证实SB202和SB204抑制微管蛋白聚合，在细胞周期的G2 / M期阻止细胞，干扰癌细胞的迁移和增殖，并增强凋亡级联反应。当在体内进行评估时，SB202对抗紫杉醇的小鼠异种移植模型表现出抗肿瘤和血管破坏作用，这强烈表明该支架具有克服癌症治疗的多药耐药性的潜力。

更新日期：2019-11-28

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