883561-04-4Relevant articles and documents
Biphenyl-4-carboxylic acid [2-(1 H -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
Mahale, Sachin,Bharate, Sandip B.,Manda, Sudhakar,Joshi, Prashant,Bharate, Sonali S.,Jenkins, Paul R.,Vishwakarma, Ram A.,Chaudhuri, Bhabatosh
, p. 9658 - 9672 (2015/02/02)
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.
Design, synthesis and biological evaluation of new tryptamine and tetrahydro-β-carboline-based selective inhibitors of CDK4
Jenkins, Paul R.,Wilson, James,Emmerson, Daniel,Garcia, Marcos D.,Smith, Matthew R.,Gray, Stephen J.,Britton, Robert G.,Mahale, Sachin,Chaudhuri, Bhabatosh
, p. 7728 - 7739 (2008/12/23)
We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-β-carboline compounds related to the natural product fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the Suzuki-Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have a CDK4 IC50 in the range 9-11 μM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a π-stacking pocket within the active site of CDK4.
