title: 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.affiliation: Chong Kun Dang Research Institute, CKD Pharmaceuticals, PO Box 74, Chonan, Korea.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Lee
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hojin
authors.initials: H
authors.lastname: Choi
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: In Taek
authors.initials: IT
authors.lastname: Lim
authors.forename: Hyun-mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Lee
authors.forename: Hee Ryong
authors.initials: HR
authors.lastname: Kang
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
authors.forename: Seung Kee
authors.initials: SK
authors.lastname: Moon
authors.forename: Dal-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Sungsook
authors.initials: S
authors.lastname: Lee
authors.forename: Nam Song
authors.initials: NS
authors.lastname: Choi
authors.forename: Kyung Joo
authors.initials: KJ
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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