Novel small molecule induces p53-dependent apoptosis in human colon cancer cells.

Using high-throughput screening with small-molecule libraries, we identified a compound, KCG165 [(2-(3-(2-(pyrrolidin-1-yl)ethoxy)-1,10b-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one)], which strongly activated p53-mediated transcriptional activity. KCG165-induced phosphorylations of p53 at Ser(6), Ser(15), and Ser(20)(,) which are all key residues involved in the activation and stabilization of p53. Consistent with these findings, KCG165 increased level of p53 protein and led to the accumulation of transcriptionally active p53 in the nucleus with the increased occupancy of p53 in the endogenous promoter region of its downstream target gene, p21(WAF1/CIP). Notably, KCG165-induced p53-dependent apoptosis in cancer cells. Furthermore, we suggested topoisomerase II as the molecular target of KCG165. Together, these results indicate that KCG165 may have potential applications as an antitumor agent.
AuthorsSang Eun Park, Yong Ki Min, Jae Du Ha, Bum Tae Kim, Woo Ghil Lee
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 358 Issue 3 Pg. 842-7 (Jul 6 2007) ISSN: 0006-291X [Print] United States
PMID17509529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 3-(2-(pyrrolidin-1-yl)ethoxy)-1,10b-dihydro-(1,2,4)triazolo(1,5-c)quinazolin-5(6H)-one
  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Quinazolinones
  • Triazoles
  • Tumor Suppressor Protein p53
  • DNA Topoisomerases, Type II
  • Antineoplastic Agents (pharmacology)
  • Apoptosis
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Nucleus (metabolism)
  • Colonic Neoplasms (genetics, pathology)
  • Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
  • DNA Topoisomerases, Type II (chemistry)
  • Dose-Response Relationship, Drug
  • Fibroblasts (metabolism)
  • Humans
  • Phosphorylation
  • Quinazolinones (pharmacology)
  • Transcriptional Activation
  • Triazoles (pharmacology)
  • Tumor Suppressor Protein p53 (metabolism)

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