Discovery of 3-(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

Guagnano, Vito; Furet, Pascal; Spanka, Carsten; Bordas, Vincent; Douget, Mickaël Le; Stamm, Christelle; Brueggen, Josef; Jensen, Michael Rugaard; Schnell, Christian; Schmid, Herbert; Wartmann, Markus; Berghausen, Joerg; Drueckes, Peter; Zimmerlin, Alfred; Bussiere, Dirksen E.; Murray, J.M.; Porta, Diana Graus

doi:10.1021/jm2006222

Cited by 401 publications

(351 citation statements)

References 53 publications

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“…This includes AZD4547 , BGJ398 (Guagnano et al, 2011), LY2874455 (Zhao et al, 2011), TAS-120 (Ochiiwa et al, 2014), ARQ 087 (Dransfield et al, 2014), PD 173074 (Dimitroff et al, 1999), JNJ-42756493 (Tabernero et al, 2015), BLU9931 (Hagel et al, 2015), DEBIO 1347 (Nakanishi et al, 2014), FGF401 (Repana et al, 2015) and BAY-1163877 (Heroult et al, 2014). Due to the large amount of drugs we will only focus on those who are being evaluated in clinical trials (Table 2).…”

Section: Selective Fgfr Tkismentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

168

156

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Section: Selective Fgfr Tkismentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

168

156

View full text Add to dashboard Cite

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“…BGJ398 is another selective inhibitor of FGFR1-3 ( 73 ). A phase I trial is currently recruiting patients with advanced solid tumors showing FGFR1 or FGFR2 amplifi cation or FGFR3 mutation.…”

Section: Selective Anti-fgfr Tkismentioning

confidence: 99%

“…Very preliminary data from clinical settings suggest that this toxicity may also represent an issue in humans. In the BGJ398 phase I trial, hyperphosphatemia was reported as controllable by the use of phosphate binders and diuretics ( 73 ). Then, the next step will be to develop specifi c and adequate toxicity management protocols and strategies.…”

Section: Selective Anti-fgfr Tkismentioning

confidence: 99%

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

et al. 2013

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The fi broblast growth factor/fi broblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifi cations, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, classspecifi c toxicity profi les and correctly designing clinical trials to address these different issues.Signifi cance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies. Cancer Discov;3(3);

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“…12,13 Thus, discovery of highly selective FGFR inhibitors is an unmet medical need. Currently, several selective FGFR inhibitors have progressed robustly into clinical trials, such as NVP-BGJ398, 14 AZD4547, 15 and CH5183284 16 (Figure 1). PD173074 (Figure 1), the first reported selective FGFR inhibitor, inhibits FGFR1 with an IC 50 value of 21.5 nM at the molecular level, while inhibiting PDGFR, c-Src and EGFR, as well as several serine/threonine kinases with 1000-fold or greater IC 50 values.…”

mentioning

confidence: 99%

Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors

Zhao

et al. 2016

ACS Med. Chem. Lett.

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Fibroblast growth factor receptors (FGFRs) are important targets for cancer therapy. Herein, we describe the design, synthesis, and biological evaluation of a novel series of 1H-pyrazolo [3,4-b]pyridine derivatives as potent and selective FGFR kinase inhibitors. On the basis of its excellent in vitro potency and favorable pharmacokinetic properties, compound 7n was selected for in vivo evaluation and showed significant antitumor activity in a FGFR1-driven H1581 xenograft model. These results indicated that 7n would be a promising candidate for further drug development. Cancer, FGFR, inhibitor, pyrazolo[3,pyridine F ibroblast growth factors (FGFs) and their receptors regulate a wide range of biological functions, including embryogenesis, tissue repair, wound healing, and angiogenesis. 1−3 The fibroblast growth factor receptor (FGFR) family comprises four highly conserved transmembrane tyrosine kinase receptors (FGFR1−4), which are differentially activated by binding to a subset of 18 FGF ligands. 3,4 Upon FGF binding, FGFR undergoes dimerization and autophosphorylation, resulting in activation of downstream signaling pathways, such as the MAPK and PLCγ pathways. 4,5 These FGFR cascades play crucial roles in key cell behaviors, such as proliferation, survival, differentiation, and migration, which makes FGFR signaling susceptible to subversion by cancer cells. 6 Dysregulation of FGFR signaling has been documented in clinical samples of bladder, lung, breast cancers, etc., 7 and aberrant FGFR activation is closely correlated with metastatic progression and poor prognosis. 8,9 Knockdown studies and pharmaceutical inhibition of FGFRs in preclinical models have further demonstrated that FGFRs are attractive targets for cancer therapy. 4,7,10 In recent years, many small molecules have been in clinical development, such as nintedanib, dovitinib, and cediranib, which are reported to target FGFR. 11 However, because of the high degree of homology of FGFRs with VEGFRs, most of these compounds have multitarget specificity, which leads to undesired side effects in their anticancer therapies. 12,13 Thus, discovery of highly selective FGFR inhibitors is an unmet medical need. Currently, several selective FGFR inhibitors have progressed robustly into clinical trials, such as NVP-BGJ398, 14 AZD4547, 15 and CH5183284 16 (Figure 1). PD173074 (Figure 1), the first reported selective FGFR inhibitor, inhibits FGFR1 with an IC 50 value of 21.5 nM at the molecular level, while inhibiting PDGFR, c-Src and EGFR, as well as several serine/threonine kinases with 1000-fold or greater IC 50 values. 17 Nevertheless, PD173074 exhibits submicromolar inhibitory activity at the cellular level against VEGFR2 (IC 50 = 100−200 nM). 17 The crystal structure of PD173074 in complex with the FGFR1 kinase domain elucidates that its high affinity and selectivity for FGFR1 stem from the presence of 3,5-dimethoxy phenyl ring that adopts an almost perpendicular orientation to the plane of the KEYWORDS:

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Discovery of 3-(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

Cited by 401 publications

References 53 publications

FGFR a promising druggable target in cancer: Molecular biology and new drugs

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors

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