2. Academic Validation
  3. Design, synthesis, and biological evaluation of pseudo-bicyclic pyrimidine-based compounds as potential EGFR inhibitors

Design, synthesis, and biological evaluation of pseudo-bicyclic pyrimidine-based compounds as potential EGFR inhibitors

  • Bioorg Chem. 2022 Sep;126:105918. doi: 10.1016/j.bioorg.2022.105918.
Ahmed Karam Farag 1,  Byung Sun Ahn 2,  Je Sik Yoo 3,  Reham Karam 4,  Eun Joo Roh 5
Affiliations

Affiliations

  • 1 Manufacturing department, Curachem Inc, Chungcheongbuk-do 28161, Republic of Korea. Electronic address: ahmed@curachem.com.
  • 2 Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
  • 3 Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, Republic of Korea.
  • 4 Virology department, Faculty of veterinary medicine, Mansoura University, Dakahlia, Egypt.
  • 5 Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, Republic of Korea. Electronic address: r8636@kist.re.kr.
PMID: 35696765 DOI: 10.1016/j.bioorg.2022.105918
Abstract

Cancer is one of the most dangerous diseases harvesting millions of lives every year globally, which mandates the development of new therapies. In this report, we designed and synthesized a novel series of compounds based on the structure of lapatinib and AF8c, a compound we developed and reported previously, to target EGFR kinase. The series was assayed against a panel of 60 Cancer cell lines at the National Cancer Institute (NCI). Compounds 4a, 4f, 4 g, and 4 l showed high efficacy against melanoma, colon, and blood cancers, with 4a being the most effective. The evaluation of the potency of 4a against the 60 cell lines in a five-dose assay revealed a significant potency compared to lapatinib against melanoma, colon, and blood cancers. In vitro Enzyme assay over 30 kinases showed significant potency against EGFR and high selectivity to EGFR among the tested kinases. A molecular modeling study of 4a and lapatinib inside the pockets of EGFR revealed that both compounds bind strongly inside the ATP-binding pocket of the EGFR kinase domain. Therefore, we present 4a as a novel EGFR kinase inhibitor with potent in vitro cellular activity against diverse types of Cancer cells.

Keywords

Cancer; Kinase; Molecular docking; Pyrimidine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146154
    EGFR Inhibitor