Dataset Information

2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors.

ABSTRACT: A series of 2-aminopyrimidine derivatives were designed and synthesized as highly selective FGFR4 inhibitors. One of the most promising compounds 2n tightly bound FGFR4 with a Kd value of 3.3 nM and potently inhibited its enzymatic activity with an IC50 value of 2.6 nM, but completely spared FGFR1/2/3. The compound selectively suppressed proliferation of breast cancer cells harboring dysregulated FGFR4 signaling with an IC50 value of 0.38 ?M. Furthermore, 2n exhibited extraordinary target specificity in a Kinome-wide screen against 468 kinases, with S(35) and S(10) selectivity scores of 0.01 and 0.007 at 1.0 ?M, respectively.

SUBMITTER: Mo C

PROVIDER: S-EPMC5430393 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors.

Mo Cheng C Zhang Zhang Z Guise Christopher P CP Li Xueqiang X Luo Jinfeng J Tu Zhengchao Z Xu Yong Y Patterson Adam V AV Smaill Jeff B JB Ren Xiaomei X Lu Xiaoyun X Ding Ke K

ACS medicinal chemistry letters 20170331 5

A series of 2-aminopyrimidine derivatives were designed and synthesized as highly selective FGFR4 inhibitors. One of the most promising compounds 2n tightly bound FGFR4 with a Kd value of 3.3 nM and potently inhibited its enzymatic activity with an IC50 value of 2.6 nM, but completely spared FGFR1/2/3. The compound selectively suppressed proliferation of breast cancer cells harboring dysregulated FGFR4 signaling with an IC50 value of 0.38 μM. Furthe ...[more]

PMID: 28523108

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Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Currently patients are treated by surgical cytoreductive surgery with the aim of reducing tumor burden to microscopic disease followed by adjuvant combined treatment with a platinum and taxane containing chemotherapy, which affords 80% of patients an initial complete response. However, Abdominal and pelvic recurrence rates are high and response to further chemotherapy is limited. Attempts at introducing biologic therapeutic agents to improve outcome in this disease are ongoing, while prognostic or predictive biomarkers that can stratify patients for treatment are still lacking. Using a 60-mer 22K oligonucleotide-based array comparative genome hybridization (CGH) platform combined with DNA isolated from microdissected tumor tissue samples, Birrer et. al. reported that the amplification of 5q31-35.3 in ovarian cancer cells is a negative prognostic indicator for patients with advanced stage high-grade serous ovarian cancer (HGSC). Further studies showed that fibroblast growth factor 1 (FGF1) located in the amplicon, may be one of the driving genes for ovarian cancer progression (Birrer et. al., 2007). Besides FGF1, located on the same amplicon is one of its receptors fibroblast growth factor receptor 4 (FGFR4), suggesting that it may also be amplified and may be another driving gene involved in ovarian cancer pathogenesis.In this study, we used microarrays to explore and compare gene expression profiles between FGFR4 knock down ovarian cancer cell lines and their corresponding parental cell lines. Two high grade serous ovarian cancer cell lines: SKOV3 and OVCA432 were selected for this study. For each of the cell lines, two different siRNA sequences which both target human FGFR4 were used. While a non-target scramble siRNA sequence was used as control. Ovarian cancer cells were transfected with siRNA using lipofectamine (Invitrogen). RNA extraction was performed 72 hours post-transfection, followed by hybridization on Affymetrix microarrays.

Dataset Information

2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors.

Publications

2-Aminopyrimidine Derivatives as New Selective Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors.

Similar Datasets

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