title: Discovery and evaluation of 3-phenyl-1H-5-pyrazolylamine-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).
abstract: Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Hsieh
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Yen
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Tsu
authors.initials: T
authors.lastname: Hsu
authors.forename: Cheng-Tai
authors.initials: CT
authors.lastname: Lu
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Chun-Wha
authors.initials: CW
authors.lastname: Chen
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Chou
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Huang
authors.forename: An-Huei
authors.initials: AH
authors.lastname: Cheng
authors.forename: Yun-I
authors.initials: YI
authors.lastname: Chang
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Tseng
authors.forename: Kuei-Rong
authors.initials: KR
authors.lastname: Yen
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D000077157:Sorafenib; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007191:Indazoles; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077157:Sorafenib; D013449:Sulfonamides; D051941:fms-Like Tyrosine Kinase 3; C568686:N1-(3-(5-(2-methyl-6-(4-methylpiperazino)-4-pyrimidinyl)amino-1H-3-pyrazolyl)phenyl)-1-benzenesulfonamide; D000096926:Benzenesulfonamides; C513486:linifanib