Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor
Pengxing He1, Shenghui Niu1, Shuai Wang1
1School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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.
Insights
WS-157 is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) discovered for solid tumor treatment. It demonstrates strong in vitro and in vivo anti-tumor activity, showing promise as an anti-lung cancer agent.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are established treatments for solid tumors.
- There is an ongoing need for novel EGFR-TKIs with improved efficacy and pharmacokinetic profiles.
Purpose of the Study:
- To report the discovery and characterization of WS-157, a novel potent and selective EGFR-TKI.
- To evaluate the in vitro and in vivo anti-tumor activity of WS-157 compared to gefitinib.
Main Methods:
- In vitro kinase inhibition assays against EGFR and related kinases.
- Cell proliferation, colony formation, and wound healing assays.
- In vivo anti-tumor efficacy studies in xenograft mouse models and pharmacokinetic evaluations.
Main Results:
- WS-157 exhibited potent inhibition against EGFR, EGFR[d746-750], and EGFR[L858R] (IC50 values 0.81-1.2 nmol/L) with selectivity over other kinases.
- WS-157 demonstrated significant antiproliferative activity, reduced colony formation, and inhibited wound healing in cancer cell lines.
- WS-157 showed superior oral anti-tumor activity in A431 xenograft models, with improved intestinal absorption, pharmacokinetics, and metabolic stability compared to gefitinib.
Conclusions:
- WS-157 is a potent and selective EGFR-TKI with significant in vitro and in vivo anti-tumor efficacy.
- WS-157 possesses favorable pharmacokinetic properties and metabolic stability.
- WS-157 represents a promising candidate for the development of novel anti-lung cancer therapeutics targeting EGFR.
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