The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study.
The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study.
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DOI：
10.1016/j.ebiom.2015.02.009
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发表时间：
2015-03-01
期刊：
影响因子：
11.1
通讯作者：
Katan, Matilda
中科院分区：
文献类型：
--
作者：
Bunney, Tom D.;Wan, Shunzhou;Thiyagarajan, Nethaji;Sutto, Ludovico;Williams, Sarah V.;Ashford, Paul;Koss, Hans;Knowles, Margaret A.;Gervasio, Francesco L.;Coveney, Peter V.;Katan, Matilda
成纤维细胞生长因子受体（FGFR）是癌症中公认的治疗靶标。我们在这里使用计算计算以及包括细胞研究，X射线晶体学以及生物物理学和生物化学测量的结合，描述了突变对FGFR1和FGFR3激酶活性和药物疗效的影响的洞察力。我们的发现表明，某些经过测试的化合物，特别是TKI258，不仅可以为FGFR主要改变的患者提供治疗机会，而且还可以为由于看门人突变而获得的耐药性。此处应用的计算方法的准确性显示了它们在药物结合研究以及对突变的功能和机理影响评估中的更广泛应用的潜力，从而有助于精确医学的努力。
FGFR中的点突变会导致药物疗效的不同特征。
FGFR1和FGFR3中的网务突变保持对TKI258的敏感性。
药物结合和变构效应的理论评估表明准确性很高。
Fibroblast growth factor receptors (FGFRs) are recognized therapeutic targets in cancer. We here describe insights underpinning the impact of mutations on FGFR1 and FGFR3 kinase activity and drug efficacy, using a combination of computational calculations and experimental approaches including cellular studies, X-ray crystallography and biophysical and biochemical measurements. Our findings reveal that some of the tested compounds, in particular TKI258, could provide therapeutic opportunity not only for patients with primary alterations in FGFR but also for acquired resistance due to the gatekeeper mutation. The accuracy of the computational methodologies applied here shows a potential for their wider application in studies of drug binding and in assessments of functional and mechanistic impacts of mutations, thus assisting efforts in precision medicine. Point mutations in FGFR can result in distinct signatures for drug efficacy. Gatekeeper mutations in FGFR1 and FGFR3 retain sensitivity to TKI258. Theoretical assessments of drug binding and allosteric effects show high level of accuracy.
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影响因子：
7.3
作者：
Choi HG;Ren P;Adrian F;Sun F;Lee HS;Wang X;Ding Q;Zhang G;Xie Y;Zhang J;Liu Y;Tuntland T;Warmuth M;Manley PW;Mestan J;Gray NS;Sim T
通讯作者：
Sim T
DOI：
10.1073/pnas.0914157107
发表时间：
2010-02-16
影响因子：
11.1
作者：
Bae, Jae Hyun;Boggon, Titus J.;Schlessinger, Joseph
通讯作者：
Schlessinger, Joseph
影响因子：
11.5
作者：
Brooks, A. Nigel;Kilgour, Elaine;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
4
作者：
Azam, Mohammad;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B