title: Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors.
abstract: Novel 2-chloro-4-anilino-quinazolines designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for inhibitory effects. EGFR and VEGFR-2 are validated targets in cancer therapy and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The biological data obtained proved the potential of 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, highlighting compound 8o, which was approximately 7-fold more potent on VEGFR-2 and approximately 11-fold more potent on EGFR compared to the prototype 7. SAR and docking studies allowed the identification of pharmacophoric groups for both kinases and demonstrated the importance of a hydrogen bond donor at the para position of the aniline moiety for interaction with conserved Glu and Asp amino acids in EGFR and VEGFR-2 binding sites.
authors.affiliation: Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil(1); Graduate Program of Chemistry (PGQu), Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Letícia de Castro
authors.initials: ML
authors.lastname: Barbosa
authors.affiliation: Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil(1); Graduate Program of Chemistry (PGQu), Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Lídia Moreira
authors.initials: LM
authors.lastname: Lima
authors.affiliation: Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil(1).
authors.forename: Roberta
authors.initials: R
authors.lastname: Tesch
authors.affiliation: Department of Chemistry, Federal Rural University of Rio de Janeiro (UFRRJ), Seropédica, RJ, Brazil.
authors.forename: Carlos Mauricio R
authors.initials: CM
authors.lastname: Sant'Anna
authors.affiliation: ProQinase GmbH, Freiburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.affiliation: ProQinase GmbH, Freiburg, Germany.
authors.forename: Michael H G
authors.initials: MH
authors.lastname: Kubbutat
authors.affiliation: ProQinase GmbH, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
authors.affiliation: Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil(1); Graduate Program of Chemistry (PGQu), Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Electronic address: ejbarreiro@ccsdecania.ufrj.br.
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Antitumor; Cancer; EGFR; Quinazoline; VEGFR-2