Identification of CKD-516: a potent tubulin polymerization inhibitor with marked antitumor activity against murine and human solid tumors.
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.
Lee
Jaekwang
J
Chong Kun Dang Research Institute, CKD Pharmaceuticals, PO Box 74, Chonan, Korea.
Kim
Soo Jin
SJ
Choi
Hojin
H
Kim
Young Hoon
YH
Lim
In Taek
IT
Yang
Hyun-mo
HM
Lee
Chang Sik
CS
Kang
Hee Ryong
HR
Ahn
Soon Kil
SK
Moon
Seung Kee
SK
Kim
Dal-Hyun
DH
Lee
Sungsook
S
Choi
Nam Song
NS
Lee
Kyung Joo
KJ
D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001577:Benzophenones; C552333:N-(4-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)thiazol-2-yl)-2-amino-3-methylbutanamide; D011355:Prodrugs; D050257:Tubulin Modulators; D014633:Valine