Discovery of [5-Amino-1-(2-methyl-3<i>H</i>-benzimidazol-5-yl)pyrazol-4-yl]-(1<i>H</i>-indol-2-yl)methanone (CH5183284/Debio 1347), An Orally Available and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor

Ebiike, Hirosato; Taka, Naoki; Matsushita, Masayuki; Ohmori, Masayuki; Takami, Kyoko; Hyohdoh, Ikumi; Kohchi, Masami; Hayase, Tadakatsu; Nishii, Hiroki; Morikami, Kenji; Nakanishi, Yoshito; Akiyama, Nukinori; Shindoh, Hidetoshi; Ishii, Nobuya; Isobe, Takehito; Matsuoka, Hirotaka

doi:10.1021/acs.jmedchem.6b01156

Cited by 33 publications

(16 citation statements)

References 29 publications

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“…Currently, several FGFR-selective inhibitors, such as AZD4547 (11), NVP-BGJ398 (12), and Debio 1347/CH5183284 (13,14), are being used in clinical trials with patients who have FGFR genetic alterations in several tumor types. In one study for gastric cancer, AZD4547 demonstrated promising efficacy in patients harboring FGFR2 amplification (15), with three out of six FGFR2amplified patients obtaining partial response on AZD4547 monotherapy.…”

Section: Introductionmentioning

confidence: 99%

Acquired JHDM1D–BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer

Sase¹,

Nakanishi²,

Aida³

et al. 2018

Molecular Cancer Therapeutics

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gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D () and between the 3rd and the 4th exon of We sequenced cDNA of the AZD-R clones and found fusion kinase, which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion..

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Section: Introductionmentioning

confidence: 99%

Acquired JHDM1D–BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer

Sase¹,

Nakanishi²,

Aida³

et al. 2018

Molecular Cancer Therapeutics

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“…After the 3D structure of the FGFR protein was reported, it was easier to design selective and potent inhibitors-targeting the FGFR. Numerous representative inhibitors exist, including AZD4547 15 , NVP-BGJ398 16 , CH5183284 17 , LY2874455 18 and JNJ-42756493 19 ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer

Xie

Cheng

Guo-liang

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1.85 ± 0.32 µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1.

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“…Moreover, aberrant signaling of FGF/FGFR has been frequently found in various cancers, making FGFR a hot therapeutic target in anticancer drug development [ 11 ]. Selective and potent FGFR inhibitors are needed, because, in general, compounds that are selective to one intended target kinase can potentially claim a more favorable safety profile than multi-target compounds [ 12 , 13 , 14 ]. Currently, several FGFR-targeted small molecules have been evaluated in clinical trials for cancer treatment, such as NVP-BGJ398 ( 1 ) [ 15 ], AZD4547 ( 2 ) [ 16 , 17 ], LY2874455 ( 3 ) [ 18 ], and CH5183284 ( 4 ) [ 19 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors

et al. 2018

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Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development.

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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

Cited by 33 publications

References 29 publications

Acquired JHDM1D–BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer

Acquired JHDM1D–BRAF Fusion Confers Resistance to FGFR Inhibition in FGFR2-Amplified Gastric Cancer

Design, synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer

Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors

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