1. Academic Validation
  2. Biphenyl-4-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-methylamide (CA224), a nonplanar analogue of fascaplysin, inhibits Cdk4 and tubulin polymerization: evaluation of in vitro and in vivo anticancer activity

Biphenyl-4-carboxylic acid [2-(1H-indol-3-yl)-ethyl]-methylamide (CA224), a nonplanar analogue of fascaplysin, inhibits Cdk4 and tubulin polymerization: evaluation of in vitro and in vivo anticancer activity

  • J Med Chem. 2014 Nov 26;57(22):9658-72. doi: 10.1021/jm5014743.
Sachin Mahale 1 Sandip B Bharate Sudhakar Manda Prashant Joshi Sonali S Bharate Paul R Jenkins Ram A Vishwakarma Bhabatosh Chaudhuri
Affiliations

Affiliation

  • 1 School of Pharmacy, De Montfort University , Leicester LE1 9BH, United Kingdom.
Abstract

Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of Cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the fact that it inhibits tubulin polymerization. Additionally, it acts as an enhancer of depolymerization for taxol-stabilized tubulin. Western blot analyses of p53-positive Cancer cells treated with compound 1 indicated upregulation of p53, p21, and p27 proteins together with downregulation of cyclin B1 and CDK1. Compound 1 selectively induces Apoptosis of SV40 large T-antigen transformed cells and significantly reduces colony formation efficiency, in a dose-dependent manner, of lung Cancer cells. It is efficacious at 1/10th of the MTD against human tumors derived from HCT-116 and NCI-H460 cells in SCID mouse models. The promising efficacy of compound 1 in human xenograft models as well as its excellent therapeutic window indicates its potential for clinical development.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111207
    99.94%, Cdk4–cyclin D1抑制剂