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.