Journal
ACTA PHARMACEUTICA SINICA B
Volume 9, Issue 6, Pages 1193-1203Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2019.06.010
Keywords
WS-157; Tyrosine kinase; EGFR inhibitor; Antitumor activity
Categories
Funding
- National Natural Science Foundation of China [81430085, 81773562, 81703326]
- Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (China) [KF-GN-201902]
- Natural Science Foundation of He'nan Province of China (China) [162300410303]
- Scientific Program of Henan Province (China) [182102310123]
- China Postdoctoral Science Foundation [2015M572123, 2018M630840, 2019T120641]
- Key Research Program of Higher Education of Henan Province (China) [18B350009]
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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. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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