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.
Park
Sang Eun
SE
Drug Discovery Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Min
Yong Ki
YK
Ha
Jae Du
JD
Kim
Bum Tae
BT
Lee
Woo Ghil
WG
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D052999:Quinazolinones / Q000494:pharmacology*; D015533:Transcriptional Activation; D014230:Triazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C521159:3-(2-(pyrrolidin-1-yl)ethoxy)-1,10b-dihydro-(1,2,4)triazolo(1,5-c)quinazolin-5(6H)-one; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052999:Quinazolinones; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D004250:DNA Topoisomerases, Type II