SB226, an inhibitor of tubulin polymerization, inhibits paclitaxel-resistant melanoma growth and spontaneous metastasis

• Published in: Cancer letters Vol. 555; p. 216046
• Main Authors: Deng, Shanshan, Banerjee, Souvik, Chen, Hao, Pochampally, Satyanarayana, Wang, Yuxi, Yun, Mi-Kyung, White, Stephen W., Parmar, Keyur, Meibohm, Bernd, Hartman, Kelli L., Wu, Zhongzhi, Miller, Duane D., Li, Wei
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.02.2023
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Binding Sites; Cell cycle arrest; Cell Line, Tumor; Cell Proliferation; Colchicine - pharmacology; Humans; Male; Melanoma - drug therapy; Mice; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Paclitaxel resistance; Polymerization - drug effects; Proliferation; Tubulin - metabolism; Tubulin colchicine-binding site inhibitor; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulin Modulators - therapeutic use; Cell cycle arrest; Tubulin colchicine-binding site inhibitor; Paclitaxel resistance; Proliferation; Apoptosis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.216046

Extensive preclinical studies have shown that colchicine-binding site inhibitors (CBSIs) are promising drug candidates for cancer therapy. Although numerous CBSIs were generated and evaluated, but so far the FDA has not approved any of them due to undesired adverse events or insufficient efficacies. We previously reported two very potent CBSIs, the dihydroquinoxalinone compounds 5 m and 5t. In this study, we further optimized the structures of compounds 5 m and 5t and integrated them to generate a new analog, SB226. X-ray crystal structure studies and a tubulin polymerization assay confirmed that SB226 is a CBSI that could disrupt the microtubule dynamics and interfere with microtubule assembly. Biophysical measurements using surface plasmon resonance (SPR) spectroscopy verified the high binding affinity of SB226 to tubulin dimers. The in vitro studies showed that SB226 possessed sub-nanomolar anti-proliferative activities with an average IC50 of 0.76 nM against a panel of cancer cell lines, some of which are paclitaxel-resistant, including melanoma, breast cancer and prostate cancer cells. SB226 inhibited the colony formation and migration of Taxol-resistant A375/TxR cells, and induced their G2/M phase arrest and apoptosis. Our subsequent in vivo studies confirmed that 4 mg/kg SB226 strongly inhibited the tumor growth of A375/TxR melanoma xenografts in mice and induced necrosis, anti-angiogenesis, and apoptosis in tumors. Moreover, SB226 treatment significantly inhibited spontaneous axillary lymph node, lung, and liver metastases originating from subcutaneous tumors in mice without any obvious toxicity to the animals’ major organs, demonstrating the therapeutic potential of SB226 as a novel anticancer agent for cancer therapy. •SB226 binds at the colchicine site in tubulin as confirmed by X-ray structure and surface plasmon resonance spectroscopy.•SB226 is highly potent and effectively overcomes paclitaxel-resistance in multiple cancer cell lines in vitro.•SB226 at low doses significantly inhibits primary tumor growth and spontaneous tumor metastasis in vivo.•SB226 at low doses induces tumor cell apoptosis, and suppresses tumor cell proliferation and angiogenesis in vivo.