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

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.