Biphenyl-4-carboxylic Acid
[2-(1<i>H</i>‑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
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Abstract
Biphenyl-4-carboxylic
acid-[2-(1<i>H</i>-indol-3-yl)-ethyl]-methylamide <b>1</b> (CA224) is a nonplanar analogue of fascaplysin (<b>2</b>) that specifically inhibits Cdk4–cyclin D1 in vitro. Compound <b>1</b> blocks the growth of cancer cells at G<sub>0</sub>/G<sub>1</sub> phase of the cell cycle. It also blocks the cell cycle at
G<sub>2</sub>/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 <b>1</b> indicated upregulation
of p53, p21, and p27 proteins together with downregulation of cyclin
B1 and Cdk1. Compound <b>1</b> 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 <b>1</b> in human xenograft models
as well as its excellent therapeutic window indicates its potential
for clinical development
