title: Discovery of quinolinone derivatives as potent FLT3 inhibitors.
abstract: Recently some fms-like tyrosine kinase 3 (FLT3) inhibitors have shown good efficacy in acute myeloid leukemia (AML) patients. In an effort to develop anti-leukemic drugs, we investigated quinolinone derivatives as novel FLT3 inhibitors. Two substituted quinolinones, KR65367 and KR65370 were subjected to FLT3 kinase activity assay and showed potent inhibition against FLT3 kinase activity in vitro, with IC50 of 2.7 and 0.57 nM, respectively. As a measure of selectivity, effects on the activity of other kinases were also tested. Both compounds have negligible activity against Met, Ron, epidermal growth factor receptor, Aurora A, Janus kinase 2, and insulin receptor; with IC50 greater than 10 μM. KR compounds showed strong growth inhibition in MV4;11 AML cells and increased the apoptotic cell death in flow cytometric analyses. A decrease in STAT5 phosphorylation by KR compounds was observed in MV4;11 cells. Furthermore, in vitro evaluation of compounds structurally related to KR65367 and KR65370 showed a good structure-activity relationship.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors: Hye Jin
authors: HJ
authors: Chung
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors: Majid Rasool
authors: MR
authors: Kamli
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors: Hyo Jeong
authors: HJ
authors: Lee
authors: Bio-organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors: Jae Du
authors: JD
authors: Ha
authors: Bio-organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
authors: Sung Yun
authors: SY
authors: Cho
authors: College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea.
authors: Jongkook
authors: J
authors: Lee
authors: College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
authors: Jae Yang
authors: JY
authors: Kong
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea. Electronic address: syhan@gnu.ac.kr.
authors: Sun-Young
authors: SY
authors: Han
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D050799:STAT5 Transcription Factor; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; Fms-like tyrosine kinase 3 (FLT3); Quinolinone