國家衛生研究院 NHRI:Item 3990099045/14883

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Title:	Development of furanopyrimidine-based orally active third-generation EGFR inhibitors for the treatment of non-small cell lung cancer
Authors:	Li, MC;Coumar, MS;Lin, SY;Lin, YS;Huang, GL;Chen, CH;Lien, TW;Wu, YW;Chen, YT;Chen, CP;Huang, YC;Yeh, KC;Yang, CM;Kalita, B;Pan, SL;Hsu, TA;Yeh, TK;Chen, CT;Hsieh, HP
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.
Date:	2023-02-07
Relation:	Journal of Medicinal Chemistry. 2023 Feb 7;66(4):2566-2588.
Link to:	http://dx.doi.org/10.1021/acs.jmedchem.2c01434
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:000936884300001
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85147938401
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Teng-Kuang Yeh] Periodical Articles [Chiung-Tong Chen] Periodical Articles [Shu-Yu Lin] Periodical Articles

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