Elkamhawy, Ahmed Paik, Sora Hassan, Ahmed H. E. Lee, Yong Sup Roh, Eun Joo 2024-01-20T00:04:33Z 2024-01-20T00:04:33Z 2021-09-03 2017-11 0045-2068 https://pubs.kist.re.kr/handle/201004/122132 Searching for hit compounds within the huge chemical space resembles the attempt to find a needle in a haystack. Cheminformatics-guided selection of few representative molecules of a rationally designed virtual combinatorial library is a powerful tool to confront this challenge, speed up hit identification and cut off costs. Herein, this approach has been applied to identify hit compounds with novel scaffolds able to inhibit EGFR kinase. From a generated virtual library, six 4-aryloxy-5-aminopyrimidine scaffold-derived compounds were selected, synthesized and evaluated as hit EGFR inhibitors. 4-Aryloxy-5-benzamidopyrimidines inhibited EGFR with IC50 1.05-5.37 mu M. Cell-based assay of the most potent EGFR inhibitor hit (10ac) confirmed its cytotoxicity against different cancerous cells. In spite of no EGFR, HER2 or VEGFR1 inhibition was elicited by 4-aryloxy-5-(thio)ureidopyrimidine derivatives, cell-based evaluation suggested them as antiproliferative hits acting by other mechanism(s). Molecular docking study provided a plausible explanation of incapability of 4-aryloxy-5-(thio) ureidopyrimidines to inhibit EGFR and suggested a reasonable binding mode of 4-aryloxy-5-benzamidopyrimidines which provides a basis to develop more optimized ligands. (C) 2017 Elsevier Inc. All rights reserved. English ACADEMIC PRESS INC ELSEVIER SCIENCE CELL LUNG-CANCER TYROSINE KINASE INHIBITORS UNIVERSE DATABASE GDB-17 TUMOR HETEROGENEITY TARGETED THERAPY SMALL MOLECULES RECEPTOR RESISTANCE SPACE VISUALIZATION Hit discovery of 4-amino-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide: A novel EGFR inhibitor from a designed small library Article 10.1016/j.bioorg.2017.10.009 1 BIOORGANIC CHEMISTRY, v.75, pp.393 - 405 BIOORGANIC CHEMISTRY 75 393 405 scie scopus 000417682200037 2-s2.0-85032742321 Biochemistry & Molecular Biology Chemistry, Organic Biochemistry & Molecular Biology Chemistry Article CELL LUNG-CANCER TYROSINE KINASE INHIBITORS UNIVERSE DATABASE GDB-17 TUMOR HETEROGENEITY TARGETED THERAPY SMALL MOLECULES RECEPTOR RESISTANCE SPACE VISUALIZATION Antiproliferative hits EGFR inhibitors Phenotypic screening Anticancer cell lines assay Pyrimidine derivatives