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

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Discovery of Novel Diaryl-Substituted Fused Heterocycles Targeting Katanin and Tubulin with Potent Antitumor and Antimultidrug Resistance Efficacy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-12 , DOI: 10.1021/acs.jmedchem.4c00878
Fuhao Jiang ₁ , Min Yu ₁ , Yuru Liang ₂ , Kuiling Ding ₂ , Yang Wang _{1,

3}

Affiliation

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.

中文翻译：

发现新型二芳基取代的稠合杂环化合物，靶向剑蛋白和微管蛋白，具有有效的抗肿瘤和抗多药耐药性功效

破坏微管动力学已成为一种有前途的癌症治疗策略。然而，耐药性仍然是阻碍微管靶向药物发展的挑战。在这项工作中，设计、合成和评估了一类新型二芳基取代的稠合杂环，其被证明是具有抗肿瘤活性的有效双卡塔宁和微管蛋白调节剂。经过三轮逐步优化，以3 H-咪唑并[4,5- b ]吡啶为核心的化合物21b显示出优异的katanin和微管蛋白靶向能力，以及显着的抗增殖和抗转移作用。机制研究表明， 21b会破坏肿瘤细胞中的微管网络，导致 G2/M 细胞周期停滞并诱导细胞凋亡。重要的是， 21b在 MDA-MB-231 和 A549/T 异种移植肿瘤模型中表现出显着的肿瘤生长抑制作用，且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，值得进一步研究作为具有潜在抗多药耐药性的双靶点抗肿瘤药物。

更新日期：2024-07-12

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