title: 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.
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.
authors.affiliation: School of Pharmacy, De Montfort University , Leicester LE1 9BH, United Kingdom.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mahale
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Manda
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.forename: Sonali S
authors.initials: SS
authors.lastname: Bharate
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jenkins
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019938:Cyclin D1 / Q000737:chemistry; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000737:chemistry*; D050257:Tubulin Modulators / Q000737:chemistry*; D015854:Up-Regulation; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D000970:Antineoplastic Agents; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D007211:Indoles; D010456:Peptides, Cyclic; D050257:Tubulin Modulators; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse