Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking

Ahmed Elkamhawy; Ahmed Karam Farag; Ambily Nath Indu Viswanath; Tarek M Bedair; Dong Gyu Leem; Kyung-Tae Lee; Ae Nim Pae; Eun Joo Roh

doi:10.1016/j.bmcl.2015.10.003

Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5147-54. doi: 10.1016/j.bmcl.2015.10.003. Epub 2015 Oct 9.

Authors

Ahmed Elkamhawy¹, Ahmed Karam Farag², Ambily Nath Indu Viswanath³, Tarek M Bedair⁴, Dong Gyu Leem⁵, Kyung-Tae Lee⁵, Ae Nim Pae³, Eun Joo Roh⁶

Affiliations

¹ Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
² Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea.
³ Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
⁴ Department of Biomedical Engineering, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea.
⁵ Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, South Korea.
⁶ Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 136-791, South Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), Daejeon 305-350, South Korea. Electronic address: r8636@kist.re.kr.

PMID: 26475520
DOI: 10.1016/j.bmcl.2015.10.003

Abstract

Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95 μM, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity.

Keywords: Antiproliferative activity; Bt-474 cell line; EGFR/HER2 dual inhibitors; Kinase panel; Molecular docking; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / pharmacology*
Receptor, ErbB-2 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Aniline Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolines
ErbB Receptors
Receptor, ErbB-2