Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine790 to methionine790 (T790M) mutants

Tianfeng Xu; Lianwen Zhang; Shilin Xu; Chao Yie Yang; Jinfeng Luo; Fang Ding; Xiaoyun Lu; Yingxue Liu; Zhengchao Tu; Shiliang Li; Duanqing Pei; Qian Cai; Honglin Li; Xiaomei Ren; Shaomeng Wang; Ke Ding

doi:10.1002/anie.201302313

Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine⁷⁹⁰ to methionine⁷⁹⁰ (T790M) mutants

Tianfeng Xu, Lianwen Zhang, Shilin Xu, Chao Yie Yang, Jinfeng Luo, Fang Ding, Xiaoyun Lu, Yingxue Liu, Zhengchao Tu, Shiliang Li, Duanqing Pei, Qian Cai, Honglin Li, Xiaomei Ren, Shaomeng Wang, Ke Ding

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Catching the mutants: Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives (see example) were identified as specific inhibitors of EGFR^T790M mutants. The compounds bound with T790M or L858R/T790M mutants with significantly lower K_d values than that with EGFR^WT. They also selectively inhibited EGFR signal transduction and proliferation of NSCLC cells harboring EGFR^L858R/T790M mutation, but were significantly less potent to cells with EGFR^WT.

Original language	English
Pages (from-to)	8387-8390
Number of pages	4
Journal	Angewandte Chemie - International Edition
Volume	52
Issue number	32
DOIs	https://doi.org/10.1002/anie.201302313
State	Published - 5 Aug 2013
Externally published	Yes

Keywords

T790M mutants
drug design
inhibitors
selectivity

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10.1002/anie.201302313

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Xu, T., Zhang, L., Xu, S., Yang, C. Y., Luo, J., Ding, F., Lu, X., Liu, Y., Tu, Z., Li, S., Pei, D., Cai, Q., Li, H., Ren, X., Wang, S., & Ding, K. (2013). Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine⁷⁹⁰ to methionine⁷⁹⁰ (T790M) mutants. Angewandte Chemie - International Edition, 52(32), 8387-8390. https://doi.org/10.1002/anie.201302313

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title = "Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine790 to methionine790 (T790M) mutants",

abstract = "Catching the mutants: Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives (see example) were identified as specific inhibitors of EGFRT790M mutants. The compounds bound with T790M or L858R/T790M mutants with significantly lower Kd values than that with EGFRWT. They also selectively inhibited EGFR signal transduction and proliferation of NSCLC cells harboring EGFRL858R/T790M mutation, but were significantly less potent to cells with EGFRWT.",

keywords = "T790M mutants, drug design, inhibitors, selectivity",

author = "Tianfeng Xu and Lianwen Zhang and Shilin Xu and Yang, \{Chao Yie\} and Jinfeng Luo and Fang Ding and Xiaoyun Lu and Yingxue Liu and Zhengchao Tu and Shiliang Li and Duanqing Pei and Qian Cai and Honglin Li and Xiaomei Ren and Shaomeng Wang and Ke Ding",

year = "2013",

month = aug,

day = "5",

doi = "10.1002/anie.201302313",

language = "英语",

volume = "52",

pages = "8387--8390",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "John Wiley and Sons Ltd",

number = "32",

}

Xu, T, Zhang, L, Xu, S, Yang, CY, Luo, J, Ding, F, Lu, X, Liu, Y, Tu, Z, Li, S, Pei, D, Cai, Q, Li, H, Ren, X, Wang, S & Ding, K 2013, 'Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine⁷⁹⁰ to methionine⁷⁹⁰ (T790M) mutants', Angewandte Chemie - International Edition, vol. 52, no. 32, pp. 8387-8390. https://doi.org/10.1002/anie.201302313

TY - JOUR

T1 - Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine790 to methionine790 (T790M) mutants

AU - Xu, Tianfeng

AU - Zhang, Lianwen

AU - Xu, Shilin

AU - Yang, Chao Yie

AU - Luo, Jinfeng

AU - Ding, Fang

AU - Lu, Xiaoyun

AU - Liu, Yingxue

AU - Tu, Zhengchao

AU - Li, Shiliang

AU - Pei, Duanqing

AU - Cai, Qian

AU - Li, Honglin

AU - Ren, Xiaomei

AU - Wang, Shaomeng

AU - Ding, Ke

PY - 2013/8/5

Y1 - 2013/8/5

N2 - Catching the mutants: Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives (see example) were identified as specific inhibitors of EGFRT790M mutants. The compounds bound with T790M or L858R/T790M mutants with significantly lower Kd values than that with EGFRWT. They also selectively inhibited EGFR signal transduction and proliferation of NSCLC cells harboring EGFRL858R/T790M mutation, but were significantly less potent to cells with EGFRWT.

AB - Catching the mutants: Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives (see example) were identified as specific inhibitors of EGFRT790M mutants. The compounds bound with T790M or L858R/T790M mutants with significantly lower Kd values than that with EGFRWT. They also selectively inhibited EGFR signal transduction and proliferation of NSCLC cells harboring EGFRL858R/T790M mutation, but were significantly less potent to cells with EGFRWT.

KW - T790M mutants

KW - drug design

KW - inhibitors

KW - selectivity

UR - https://www.scopus.com/pages/publications/84882255210

U2 - 10.1002/anie.201302313

DO - 10.1002/anie.201302313

M3 - 文章

C2 - 23804305

AN - SCOPUS:84882255210

SN - 1433-7851

VL - 52

SP - 8387

EP - 8390

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 32

ER -

Pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives as selective inhibitors of EGFR threonine⁷⁹⁰ to methionine⁷⁹⁰ (T790M) mutants

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