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

Abstract

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 (IC 50 = 1.5 μM) and remarkable antiproliferative potency against four cancer cell lines with an average IC 50 of 30 nM, better than colchicine and the hit compound 1f (IC 50 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.

Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity

“…CA-4P 6 , AVE8062 7 , BNC-105p 8 , and VERU-111 9 ; Figure 1 ) have been or are being studied in clinical trials due to their significant antitumor activities. Additionally, many groups also have reported potent anticancer effective CBSIs with different chemical structure types 10–17 , and the arylamide tubulin inhibitors have also attracted much attention because of their strong antitumor abilities 18–21 . For example, compound 1 18 , benzamide derivative 2 19 , and N -benzylbenzamide derivative 3 20 could potently inhibit the polymerisation of tubulin and exhibit significant antiproliferative activities on several cancer cell lines.…”

Review; Recent approaches on Tubulin Polymerization inhibitors (2018-2022)

“…Chen and his team(L. Chen et al, 2022) have designed and synthesized a new series of 2-(substituted amino)-[1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Compound 15 caused G2/M arrest, triggered cell death in HeLa cells, and shown strong tubulin polymerization inhibitory action with an IC50 value of 4.9 µM, which is equivalent to CA-4 (IC50 = 4.2 µM).…”

Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction

“…Tubulin colchicine-binding site inhibitors (CBSIs, a class of microtubule destabilizers), such as colchicine, nocodazole, and SIX2G, have been reported to be effective in triggering ICD (Figure A). In addition, some CBSIs have been found to have immunomodulatory effects (Figure A). − Meanwhile, considering the advantages of CBSIs such as significant antiproliferative activity, simple structure, and overcoming drug resistance, it is extremely attractive to develop novel CBSIs with ICD induction ability.…”