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N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer

Authors' Affiliations: ¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College; ² State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China; ³ Department of Chemistry, Georgia State University, Atlanta, Georgia; and ⁴ Department of Medicine, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Jian-Dong Jiang, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Tiantan Xili, Beijing 100050, People's Republic of China. Phone: 86-10-63165290; Fax: 86-10-63017302; E-mail: jiang.jdong{at}163.com or David W. Boykin, E-mail: dboykin{at}gsu.edu.

Purpose: We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide (IG-105). This work investigates its anticancer effect and mechanism.

Experimental Design: Anticancer efficacy was evaluated at the molecular target, cancer cells and nude mice. The mechanism was explored at submolecular, molecular, and cellular levels.

Results: IG-105 showed a potent activity against human leukemia and solid tumors in breast, liver, prostate, lung, skin, colon, and pancreas with IC₅₀ values between 0.012 and 0.298 µmol/L. It was also active in drug-resistant tumor cells and not a P-glycoprotein substrate. It inhibited microtubule assembly followed by M-phase arrest, Bcl-2 inactivation, and then apoptosis through caspase pathways. The colchicine pocket on tubulin is the binding site of IG-105. Nude mice experiments showed that IG-105 monotherapy at 100 mg/kg i.p. (q2d) yielded 81% inhibition of Bel-7402 hepatoma growth and at 275 mg/kg i.p. (q2d) completely inhibited the tumor growth. MCF-7 breast cancer in nude mice showed a similar therapeutic response to IG-105. Acute toxicity of IG-105 was not found even at 1,000 mg/kg i.p. In combination with oxaliplatin or doxorubicin, IG-105 converted each of these subcurative compounds into a curative treatment with complete inhibition for tumor growth in the hepatoma-bearing nude mice. The combination was more active than either drug. In no experiment was toxicity increased by combination chemotherapy.

Conclusions: IG-105 inhibits microtubule assembly by binding at colchicine pocket. It shows a potent anticancer activity in vitro and in vivo and has good safety in mice. We consider IG-105 merits further investigation.