國家衛生研究院 NHRI:Item 3990099045/7222

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Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/7222

Title:	Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: The role of the DFG motif in the design of epidermal growth factor receptor inhibitors
Authors:	Peng, YH;Shiao, HY;Tu, CH;Liu, PM;Hsu, JT;Amancha, PK;Wu, JS;Coumar, MS;Chen, CH;Wang, SY;Lin, WH;Sun, HY;Chao, YS;Lyu, PC;Hsieh, HP;Wu, SY
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.
Date:	2013-05
Relation:	Journal of Medicinal Chemistry. 2013 May;56(10):3889-3903.
Link to:	http://dx.doi.org/10.1021/jm400072p
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000319650100010
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84878095831
Appears in Collections:	[John Tsu-An Hsu] Periodical Articles [Yu-Sheng Chao(2002-2013)] Periodical Articles [Hsing-Pang Hsieh] Periodical Articles [Su-Ying Wu] Periodical Articles

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