The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor

Nakanishi, Yoshito; Akiyama, Nukinori; Tsukaguchi, Toshiyuki; Fujii, Toshihiko; Sakata, Kiyoaki; Sase, Hitoshi; Isobe, Takehito; Morikami, Kenji; Shindoh, Hidetoshi; Mio, Toshiyuki; Ebiike, Hirosato; Taka, Naoki; Aoki, Yuko; Ishii, Nobuya

doi:10.1158/1535-7163.mct-14-0248

Cited by 111 publications

(107 citation statements)

References 48 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%

“…This pan-FGFR inhibitor has shown great selectivity in a wide panel of cell lines and also in in vivo models with FGFR alterations, DEBIO 1347 is of great interest because it can inhibit a gatekeeper FGFR2 mutation (V564F) that cause resistance to other drugs (AZD4547 or dovitinib, for example) (Nakanishi et al, 2014). A phase I study in advanced solid tumors is currently being carried out (NCT01948297).…”

Section: Debio 1347mentioning

confidence: 99%

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

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

162

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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%

Section: Debio 1347mentioning

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

179

162

View full text Add to dashboard Cite

show abstract

“…CH5183284/Debio 1347 (FGFR inhibitor), CH4987655 (MEK inhibitor), CH5126766 (RAF-MEK inhibitor), and CH5132799 (PI3K inhibitor) were synthesized at Chugai Pharmaceutical Co. Ltd., as previously described (7,(16)(17)(18). AZD4547 was synthesized at Chugai Pharmaceutical Co. Ltd. (patent publication WO2008075068).…”

Section: Reagents and Cell Linesmentioning

confidence: 99%

“…Acquired mutations in target genes or downstream components are major mechanisms of resistance (5)(6)(7)(8)(9)(10)(11)(12)(13). Although acquired FGFR mutations have not yet been identified in patients, several FGFR mutations that confer resistance to FGFR inhibitors have been reported (7,14). Because cancer cells continue to utilize the pathway to which they are originally addicted, they acquire some genetic alterations to reactivate the pathway.…”

Section: Introductionmentioning

confidence: 99%

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

Nakanishi¹,

Mizuno²,

Sase³

et al. 2015

Molecular Cancer Therapeutics

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Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.

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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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The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor

Abstract: The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrange-

Cited by 111 publications

References 48 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

ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor

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

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