title: Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors.
abstract: FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50-100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Lu
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xi
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Jin
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China. Electronic address: jai@simm.ac.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China. Electronic address: mygeng@simm.ac.cn.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China. Electronic address: yhhu@simm.ac.cn.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D017468:Receptors, Fibroblast Growth Factor; C545373:ponatinib; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Anticancer; FGFR; Inhibitor; KDR; Ponatinib