Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Letter Article

Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

Author(s): Yan Zhang and Niefang Yu*

Volume 17, Issue 11, 2020

Page: [1330 - 1341] Pages: 12

DOI: 10.2174/1570180817999200608140628

Price: $65

Abstract

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity.

Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors.

Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase.

Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1.

Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.

Keywords: Fibroblast growth factor, FGFR, antitumor activity, kinase inhibitor, 5-amino-1H-pyrazole-1-carbonyl, molecular operating environment.

« Previous Next »
Graphical Abstract

[1]
Touat M, Ileana E, Postel-Vinay S, André F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res 2015; 21(12): 2684-94.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2329] [PMID: 26078430]
[2]
Kelleher FC, O’Sullivan H, Smyth E, McDermott R, Viterbo A. Fibroblast growth factor receptors, developmental corruption and malignant disease. Carcinogenesis 2013; 34(10): 2198-205.
[http://dx.doi.org/10.1093/carcin/bgt254] [PMID: 23880303]
[3]
Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 2009; 8(3): 235-53.
[http://dx.doi.org/10.1038/nrd2792] [PMID: 19247306]
[4]
Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumorsby next-generation sequencing. Clin Cancer Res 2016; 22(1): 259-67.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-3212] [PMID: 26373574]
[5]
Turner N, Pearson A, Sharpe R, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 2010; 70(5): 2085-94.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3746] [PMID: 20179196]
[6]
Collin M-P. * Mario Lobell, Walter Hbsch, Dirk Brohm,Hartmut Schirok,Rolf Jautelat,Klemens Lustig, Ulf Bçmer, Verena Vçhringer, Mlanie Hroult,Sylvia Grnewald,and Holger Hess-Stumpp. Discovery of Rogaratinib(BAY1163877):a pan-FGFR Inhibitor. ChemMedChem 2018; 13: 1-10.
[7]
Herbert C, Lassalle G, Alcouffe C, Bono F. Approaches targeting the FGF-FGFR system: a review of the recent patent literature and associated advanced therapeutic agents. Pharm Pat Anal 2014; 3(6): 585-612.
[http://dx.doi.org/10.4155/ppa.14.45] [PMID: 25489913]
[8]
Guagnano V, Furet P, Spanka C, et al. GrausPorta,D.Discoveryof3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 2011; 54: 7066-83.
[http://dx.doi.org/10.1021/jm2006222] [PMID: 21936542]
[9]
Gavine PR, Mooney L, Kilgour E, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 2012; 72(8): 2045-56.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-3034] [PMID: 22369928]
[10]
Ebiike H, Taka N, Matsushita M, et al. Discovery of [5-Amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone (CH5183284/Debio 1347), An Orally Available and Selective Fibroblast Growth Factor Receptor (FGFR). Inhibitor J Med Chem 2016; 59(23): 10586-600.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01156] [PMID: 27933954]
[11]
Zhao G, Li WY, Chen D, et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol Cancer Ther 2011; 10(11): 2200-10.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0306] [PMID: 21900693]
[12]
Perera TPS, Jovcheva E, Mevellec L, et al. Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor. Mol Cancer Ther 2017; 16(6): 1010-20.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0589] [PMID: 28341788]
[13]
Phillip Cc. Liu; Liangxing, Wu; Koblish, Holly; Bowman, Kevin; Zhang, Yue; Klabe, Ronald; Leffet, Lynn; DiMatteo, Darlise; Rupar, Mark; Gallagher, Karen; Hansbury, Michael Colin Zhang Chunhong He Paul Collier MaryAnne Covington Richard Wynn Swamy Yeleswaram Kris Vaddi Timothy Burn Wenqing Yao Reid Huber Peggy Scherle Gregory Hollis. Preclinical characterization of the selective FGFR inhibitor. American Association for Cancer Research (AACR), 75, 771.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0589] [PMID: 28341788]
[14]
Wang Y, Cai Y, Ji J, et al. Discovery and identification of new non-ATP competitive FGFR1 inhibitors with therapeutic potential on non-small-cell lung cancer. Cancer Lett 2014; 344(1): 82-9.
[http://dx.doi.org/10.1016/j.canlet.2013.10.016] [PMID: 24513267]
[15]
Kumar SB, Narasu L, Gundla R, Dayam R. J a r p, S. Fibroblast growth factor receptor inhibitors. Curr Pharm Des 2013; 19(4): 687-701.
[http://dx.doi.org/10.2174/138161213804581963] [PMID: 23016864]
[16]
Liang G, Liu Z, Wu J, Cai Y, Li X. Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol Sci 2012; 33(10): 531-41.
[http://dx.doi.org/10.1016/j.tips.2012.07.001] [PMID: 22884522]
[17]
Hallinan N, Finn S, Cuffe S, Rafee S, O’Byrne K, Gately K. Targeting the fibroblast growth factor receptor family in cancer. Cancer Treat Rev 2016; 46: 51-62.
[http://dx.doi.org/10.1016/j.ctrv.2016.03.015] [PMID: 27109926]
[18]
Wang X, Chen D, Yu S, et al. Synthesis and Evaluation of Biological and Antitumor Activities of Tetrahydrobenzothieno[2,3-d]Pyrimidine Derivatives as Novel Inhibitors of FGFR1. Chem Biol Drug Des 2016; 87(4): 499-507.
[http://dx.doi.org/10.1111/cbdd.12687] [PMID: 26575787]
[19]
Ye F, Chen L, Hu L, et al. Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs. Bioorg Med Chem Lett 2015; 25(7): 1556-60.
[http://dx.doi.org/10.1016/j.bmcl.2015.02.010] [PMID: 25736993]
[20]
Traxler P, Furet P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther 1999; 82(2-3): 195-206.
[http://dx.doi.org/10.1016/S0163-7258(98)00044-8] [PMID: 10454197]
[21]
Wang Y, Li L, Fan J, et al. Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors. J Med Chem 2018; 61(20): 9085-104.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01843] [PMID: 29522671]
[22]
Nakanishi Y, Akiyama N, Tsukaguchi T, et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther 2014; 13(11): 2547-58.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0248] [PMID: 25169980]
[23]
Bae JM, Wen X, Kim T-S, et al. Fibroblast Growth Factor Receptor 1 (FGFR1) Amplification Detected by Droplet Digital Polymerase Chain Reaction (ddPCR) Is a Prognostic Factor in Colorectal Cancers. Cancer Res Treat 2020; 52(1): 74-84.
[http://dx.doi.org/10.4143/crt.2019.062] [PMID: 31096734]
[24]
Tucker JA, Klein T, Breed J, et al. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure 2014; 22(12): 1764-74.
[http://dx.doi.org/10.1016/j.str.2014.09.019] [PMID: 25465127]

Rights & Permissions Print Cite
Article Metrics
11
© 2025 Bentham Science Publishers | Privacy Policy