A novel approach to the discovery of small-molecule ligands of CDK2.
A novel approach to the discovery of small-molecule ligands of CDK2.
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DOI：
10.1002/cbic.201200316
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发表时间：
2012-09-24
期刊：
影响因子：
3.2
通讯作者：
Schoenbrunn, Ernst
中科院分区：
文献类型：
--
作者：
Martin, Mathew P.;Alam, Riazul;Betzi, Stephane;Ingles, Donna J.;Zhu, Jin-Yi;Schoenbrunn, Ernst
关键词：
In an attempt to identify novel small molecule ligands of CDK2 with potential as allosteric inhibitors, we devised a robust and cost-effective fluorescence-based high-throughput screening assay. The assay is based on the specific interaction of CDK2 with the extrinsic fluorophore 8-anilino-1-naphthalene sulfonate (ANS), which binds to a large allosteric pocket adjacent to the ATP site. Hit compounds which displace ANS directly or indirectly from CDK2 are readily classified as ATP site binders or allosteric ligands through the use of staurosporine, which blocks the ATP site without displacing ANS. Pilot screening of 1,453 compounds led to the discovery of 12 compounds with displacement activities (EC50 values) ranging from 6 to 44 μM, all of which were classified as ATP site-directed ligands. Four new Type I inhibitor scaffolds were confirmed by X-ray crystallography. While this small compound library contained only ATP-site directed ligands, the application of this assay to large compound libraries has the potential to reveal previously unrecognized chemical scaffolds suitable for structure-based design of CDK2 inhibitors with new mechanisms of action.
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影响因子：
7.3
作者：
Jadhav A;Ferreira RS;Klumpp C;Mott BT;Austin CP;Inglese J;Thomas CJ;Maloney DJ;Shoichet BK;Simeonov A
通讯作者：
Simeonov A
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/j.bbapap.2009.10.002
发表时间：
2010-03-01
影响因子：
3.2
作者：
Echalier, Aude;Endicott, Jane A.;Noble, Martin E. M.
通讯作者：
Noble, Martin E. M.
DOI：
10.1073/pnas.0812413106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
通讯作者：
Demetri, George D.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH