2. Academic Validation
  3. Discovery of potent antiproliferative agents from selected oxygen heterocycles as EGFR tyrosine kinase inhibitors from the U.S. National Cancer Institute database by in silico screening and bioactivity evaluation

Discovery of potent antiproliferative agents from selected oxygen heterocycles as EGFR tyrosine kinase inhibitors from the U.S. National Cancer Institute database by in silico screening and bioactivity evaluation

  • Bioorg Med Chem Lett. 2022 Feb 15;58:128524. doi: 10.1016/j.bmcl.2021.128524.
Nattanan Jiwacharoenchai 1,  Rungroj Saruengkhanphasit 2,  Worawat Niwetmarin 2,  Supaporn Seetaha 3,  Kiattawee Choowongkomon 4,  Somsak Ruchirawat 5,  Chatchakorn Eurtivong 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand; Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, Bangkok 10900, Thailand.
  • 2 Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand.
  • 3 Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
  • 4 Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand; Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok 10900, Thailand. Electronic address: [email protected].
  • 5 Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand; Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Commission on Higher Education (CHE), Ministry of Education, Bangkok 10400, Thailand.
  • 6 Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Commission on Higher Education (CHE), Ministry of Education, Bangkok 10400, Thailand. Electronic address: [email protected].
PMID: 34995690 DOI: 10.1016/j.bmcl.2021.128524
Abstract

A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC50 values between 0.95 and 17.71 μM against overexpressed EGFR-TK Cancer cell lines: A431 and HeLa. NSC107228 displayed the strongest antiproliferative effects with IC50 values of 2.84 and 0.95 μM against A431 and HeLa Cancer cell lines, respectively. Three compounds, NSC81111, NSC381467 and NSC114126 inhibited EGFR-TK with IC50 values between 0.15 and 30.18 nM. NSC81111 was the best inhibitor with IC50 = 0.15 nM. Molecular docking analysis of the 3 compounds predicted hydrogen bonding and hydrophobic interactions with key residues were important for the bioactivities observed. Furthermore, calculations of the physicochemical properties suggest the compounds are drug-like and are potentially active orally.

Keywords

Antiproliferative; EGFR; Molecular docking; Similarity; Virtual screening.

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