Abstract：
Disrupting microtubule dynamics has emerged as a promising strategy for cancer treatment. However, drug resistance remains a challenge hindering the development of microtubule-targeting agents. In this work, a novel class of diaryl substituted fused heterocycles were designed, synthesized, and evaluated, which were demonstrated as effective dual katanin and tubulin regulators with antitumor activity. Following three rounds of stepwise optimization, compound 21b, featuring a 3H-imidazo[4,5-b]pyridine core, displayed excellent targeting capabilities on katanin and tubulin, along with notable antiproliferative and antimetastatic effects. Mechanistic studies revealed that 21b disrupts the microtubule network in tumor cells, leading to G2/M cell cycle arrest and apoptosis induction. Importantly, 21b exhibited significant inhibition of tumor growth in MDA-MB-231 and A549/T xenograft tumor models without evident toxicity and side effects. In conclusion, compound 21b presents a novel mechanism for disrupting microtubule dynamics, warranting further investigation as a dual-targeted antitumor agent with potential antimultidrug resistance properties.
摘要：
破坏微管动力学已成为癌症治疗的有希望的策略。然而,耐药性仍然是阻碍微管靶向剂发展的挑战。在这项工作中,设计了一类新的二芳基取代的稠合杂环，合成，并评估，被证明是具有抗肿瘤活性的有效的双重katanin和微管蛋白调节剂。经过三轮逐步优化，化合物21b，具有3H-咪唑并[4,5-b]吡啶核心，在卡塔宁和微管蛋白上显示出出色的靶向能力，以及显著的抗增殖和抗转移作用。机制研究表明，21b破坏肿瘤细胞中的微管网络，导致G2/M细胞周期停滞和凋亡诱导。重要的是,图21b在MDA-MB-231和A549/T异种移植肿瘤模型中表现出对肿瘤生长的显著抑制,而没有明显的毒性和副作用。总之,化合物21b提出了一种破坏微管动力学的新机制，作为具有潜在抗多药物耐药特性的双靶向抗肿瘤剂，有必要进一步研究。
