Rational Design of Potent and Selective EGFR Tyrosine Kinase Inhibitors as Anticancer Agents

Authors: Ghosh S.; Liu X.Ping; Zheng Y.; Uckun F.M.

Source: Current Cancer Drug Targets, Volume 1, Number 2, August 2001 , pp. 129-140(14)

Publisher: Bentham Science Publishers

Abstract:

Increasing knowledge of the structure and function of the Epidermal Growth Factor Receptor (EGFR) subfamily of tyrosine kinases, and of their role in the initiation and progression of various cancers has led to the search for inhibitors of signaling molecules that may prove to be important in cancer therapy. The complex nature of EGFR biology allows for potential opportunities for EGFR inhibitors in a number of areas of cancer therapy, including proliferative, angiogenic, invasive, and metastatic aspects. Different approaches have been used to target either the extracellular ligand-binding domain of the EGFR or the intracellular tyrosine kinase region that results in interference with its signaling pathways that modulate cancer-promoting responses. Examples of these include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents that target the extracellular ligand binding region of EGFR, and small molecule inhibitors that target the intracellular kinase domain and act by interfering with ATP binding to the receptor. During the past 3 years, significant progress has been made towards the identification of new structural classes of small molecule inhibitors that show high potency and specificity towards EGFR. The search for new small molecules that inhibit kinases has included traditional approaches like the testing of natural products, random screening of chemical libraries, the use of classical structure-activity-relationship studies, and the incorporation of structure-based drug design and combinatorial chemistry techniques. There has been a significant improvement in the development of selective EGFR inhibitors with the use of a structure-based design approach employing a homology model of the EGFR kinase domain. Molecular modeling procedures have been used to generate novel molecules that are complementary in shape and electrostatics to the EGFR kinase domain topography. This review focuses on some examples of the successful use of this method.

Keywords: Selective EGFR; Tyrosine Kinase Inhibitors; Protein tyrosine kinases (PTK); phosphatidylinositol; MAb-Ricin; anilino moieties; dianilinophthalimide; LFM-A12; Matrigel matrix

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568009013334188

Publication date: 2001-08-01

• Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes, genes.
  Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cancer.
  As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.

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• In this Subject: Oncology ,  Pharmacology
• By this author: Ghosh S. ;  Liu X.Ping ;  Zheng Y. ;  Uckun F.M.

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