Discovery of Novel Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy

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.

靶向干扰微管动力学已成为癌症治疗领域极具潜力的策略之一。然而，多药耐药性仍是阻碍微管靶向药物研发的核心挑战。本研究设计、合成并评价了一类全新的二芳基取代稠合杂环化合物，该类化合物被证实为兼具抗肿瘤活性的双靶点调节剂，可同时靶向调控剑蛋白（katanin）与微管蛋白（tubulin）。历经三轮逐步优化后，以3H-咪唑并[4,5-b]吡啶为母核的化合物21b展现出对剑蛋白与微管蛋白的优异靶向结合能力，同时具备显著的抗增殖与抗转移活性。机制研究显示，化合物21b可破坏肿瘤细胞内的微管网络，进而引发细胞周期G2/M期阻滞并诱导细胞凋亡。尤为重要的是，化合物21b在MDA-MB-231与A549/T异种移植瘤模型中可显著抑制肿瘤生长，且未观察到明显的毒性与不良反应。综上，化合物21b通过全新的微管动力学干扰机制发挥抗肿瘤作用，作为兼具潜在多药耐药逆转活性的双靶点抗肿瘤候选药物，值得开展进一步的深入研究。