Discovery of Novel Acridane-Based Tubulin Polymerization Inhibitors with Anticancer and Potential Immunomodulatory...

A series of novel acridane-based tubulin polymerization inhibitors were designed, synthesized, and bioevaluated as anticancer agents. The most potent compound NT-6 exhibited high tubulin polymerization inhibitory activity (IC₅₀ = 1.5 μM) and remarkable antiproliferative potency against four cancer cell lines with an average IC₅₀ of 30 nM, better than colchicine and the hit compound 1f (IC₅₀ of 65 and 126 nM, respectively). In addition, NT-6 (10 mg/kg) exerted excellent antitumor efficacy in a melanoma tumor model with a tumor growth inhibition (TGI) of 65.1% without apparent toxicity. Importantly, the combination of NT-6 with a small-molecule PD-L1 inhibitor NP-19 decreased tumor burden significantly (TGI% = 77.6%). Moreover, the combination of NT-6 with NP-19 enhanced the antitumor immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of antitumor CD8⁺ effector T cells in tumor tissues. Collectively, NT-6 represents a novel tubulin polymerization inhibitor with immunopotentiating effects.