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Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor.


ABSTRACT: EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of WS-157 from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. WS-157 showed excellent inhibitory activities against EGFR (IC50 = 0.81 nmol/L), EGFR[d746-750] (IC50 = 1.2 nmol/L) and EGFR[L858R] (IC50 = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. WS-157 also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that WS-157 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, WS-157 showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that WS-157 has strong antitumor activity in vitro and in vivo, and could be used for the development of anti-lung cancer agent targeting EGFR.

SUBMITTER: He P 

PROVIDER: S-EPMC6900553 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor.

He Pengxing P   Niu Shenghui S   Wang Shuai S   Shi Xiaojing X   Feng Siqi S   Du Linna L   Zhang Xuyang X   Ma Zhilu Z   Yu Bin B   Liu Hongmin H  

Acta pharmaceutica Sinica. B 20190628 6


EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of <b>WS-157</b> from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. <b>WS-157</b> showed excellent inhibitory activities against EGFR (IC<sub>50</sub> = 0.81 nmol/L), EGFR<sup>[d746-750]</sup> (IC<sub>50</sub> = 1.2 nmol/L) and EGFR<sup>[L858R]</sup> (IC<sub>50</sub> = 1.1 nmol/L), but  ...[more]

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