Identification of CKD-516: a potent tubulin polymerization inhibitor with marked antitumor activity against murine and human solid tumors.

Abstract

Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SAR analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (l)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.

• Authors: Jaekwang Lee, Soo Jin Kim, Hojin Choi, Young Hoon Kim, In Taek Lim, Hyun-mo Yang, Chang Sik Lee, Hee Ryong Kang, Soon Kil Ahn, Seung Kee Moon, Dal-Hyun Kim, Sungsook Lee, Nam Song Choi, Kyung Joo Lee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 17 Pg. 6337-54 (Sep 09 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20690624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzophenones
• N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide
• Prodrugs
• Tubulin Modulators
• Valine

Topics

• Animals
• Benzophenones (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Transplantation, Heterologous
• Tubulin Modulators (chemical synthesis, chemistry, pharmacology)
• Valine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)