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.

A perspective on vascular disrupting agents that interact with tubulin: preclinical tumor imaging and biological assessment

“…A compilation of VDAs currently in human clinical trials that function, in part, through a tubulin mechanism include: CA4P11-13, AVE806214, CA1P15-17, MPC-682718, ABT-75119, TZT-102720, CYT99721,22, MN-02923, NPI-235824, BNC105P25, EPC240726-28, CKD-51629.…”

Anticancer Activity of Stilbene‐Based Derivatives

“…Unlike resveratrol that exhibits higher antiproliferative activity in the E conformation, some Z isomers of methoxylated stilbenes and relatedc ompounds have shown higher antiproliferative or anti-metastatic activity than their E isomers, but they isomerize during storage, administration and during metabolism in liver microsomes. [55][56][57] (Z)-and (E)-stilbened erivatives have been reviewed for their cytotoxic anda ntitubulin properties. [40] SAR analysis and virtual screening conducted on aw ide range of stilbene analogues have elucidated the importance of the Z configuration of the olefinicb ridge for cytotoxicity and these studies were useful in the design of novel agents with improved antimitotic activity.…”

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

“…In the presence of sodium, compound 191 with large conjugated system could react with 1,2,4-triazole ring to produce anticancer aryl triazole 192 in low yields ranging from 30% to 38% (Scheme 82) [267]. The occurrence of this N-arylation substitution might be attributed to the presence of electron withdrawing conjugated carbonyl group and five-membered heterocycle in linkage with benzene ring.…”