title: In silico identification of novel EGFR inhibitors with antiproliferative activity against cancer cells.
abstract: Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase activity by small molecules has proved effective for the treatment of cancer. To the best of our knowledge, the crystal structure of EGFR has been used for the first time to identify novel inhibitor chemotypes by docking-based in silico screening of a large virtual chemical library followed up by experimental validation. We identified several compounds with antiproliferative effects on cancer cells. Amongst them, a C(4)-N(1)-substituted pyrazolo[3,4-d]pyrimidine MSK-039 (39) was discovered as a low-micromolar inhibitor of EGFR tyrosine kinase activity. The predicted binding mode of 39 opens a new avenue toward the optimization of novel chemical entities to develop potent and selective inhibitors of EGFR signaling.
authors.affiliation: Molsoft LLC, 3366 N. Torrey Pines Ct. Ste. 300, La Jolla, CA 92037, USA. claudio@molsoft.com
authors.forename: Claudio N
authors.initials: CN
authors.lastname: Cavasotto
authors.forename: María A
authors.initials: MA
authors.lastname: Ortiz
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Abagyan
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Piedrafita
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors