Discovery of WS-157 as a highly potent,selective and orally active EGFR inhibitor |
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Institution: | 1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China;2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China |
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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), EGFRd746−750] (IC50 = 1.2 nmol/L) and EGFRL858R] (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. |
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Keywords: | Tyrosine kinase EGFR inhibitor Antitumor activity |
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