title: Targeting the dimerization of epidermal growth factor receptors with small-molecule inhibitors.
abstract: The epidermal growth factor (EGF) receptor is a receptor tyrosine kinase involved in the control of cell proliferation, and its overexpression is strongly associated with a variety of aggressive cancers. For example, 70-80% of metaplastic (cancer cells of mixed type) breast carcinomas overexpress EGF receptors. In addition, the EGF receptor is a highly significant contributor to common brain tumors (glioblastoma multiforme), both in initiation and progression (Huang P.H., Xu A.M., White F.M. (2009) Oncogenic EGFR signaling networks in glioma. Sci Signal;2:re6.). Brain metastases, an unmet medical need, are also common in metastatic cancer associated with overexpression of EGF receptors. Formation of EGF receptor homodimers is essential for kinase activation and was the basis for exploring direct inhibition of EGF receptor activation by blocking dimerization with small molecules. While inhibitors of protein/protein interactions are often considered difficult therapeutic targets, NSC56452, initially identified by virtual screening, was shown experimentally to inhibit EGF receptor kinase activation in a dose-dependent manner. This compound blocked EGF-stimulated dimer formation as measured by chemical cross-linking and luciferase fragment complementation. The compound was further shown to inhibit the growth of HeLa cells. This first-generation lead compound represents the first drug-like, small-molecule inhibitor of EGF receptor activation that is not directed against the intracellular kinase domain.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Robert Y C
authors.initials: RY
authors.lastname: Yang
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Yang
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Pike
authors.forename: Garland R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D055503:Protein Multimerization / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D066246:ErbB Receptors
references.citation: Br J Cancer. 2004 Oct 18;91(8):1532-42
references.pmid: 15480434
references.citation: Cancer Cell. 2005 Apr;7(4):301-11
references.pmid: 15837620
references.citation: Cell. 2002 Sep 20;110(6):775-87
references.pmid: 12297050
references.citation: Cell. 2002 Sep 20;110(6):763-73
references.pmid: 12297049
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):112-7
references.pmid: 18165319
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2965-9
references.pmid: 1557402
references.citation: Nat Rev Cancer. 2007 Mar;7(3):169-81
references.pmid: 17318210
references.citation: Br J Cancer. 2003 Sep 1;89(5):899-906
references.pmid: 12942124
references.citation: Mol Cell. 2003 Feb;11(2):507-17
references.pmid: 12620237
references.citation: Biochemistry. 1987 Mar 10;26(5):1443-51
references.pmid: 3494473
references.citation: Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6788-95
references.pmid: 18006781
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12288-93
references.pmid: 15284440
references.citation: Nat Rev Drug Discov. 2004 Jul;3(7):549-50
references.pmid: 15272498
references.citation: Oncogene. 2002 Jan 3;21(1):119-27
references.pmid: 11791182
references.citation: Cancer Res. 2006 May 15;66(10):5201-8
references.pmid: 16707444
references.citation: J Biol Chem. 2007 Dec 28;282(52):37815-25
references.pmid: 17971444
references.citation: J Biol Chem. 2009 Mar 20;284(12):7474-82
references.pmid: 19171934
references.citation: J Chem Inf Model. 2006 Jan-Feb;46(1):401-15
references.pmid: 16426074
references.citation: Mol Cell Biol. 2005 Sep;25(17):7734-42
references.pmid: 16107719
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: J Comput Chem. 2007 Apr 30;28(6):1145-52
references.pmid: 17274016
references.citation: Cell. 2006 Jun 16;125(6):1137-49
references.pmid: 16777603
references.citation: Nat Genet. 2005 Dec;37(12):1315-6
references.pmid: 16258541
references.citation: J Biol Chem. 2004 May 21;279(21):22387-98
references.pmid: 15016810
references.citation: Nature. 1984 May 31-Jun 6;309(5967):418-25
references.pmid: 6328312
references.citation: Methods Mol Biol. 2008;439:339-52
references.pmid: 18370114
references.citation: J Biol Chem. 2005 Aug 26;280(34):30392-9
references.pmid: 15994331
references.citation: J Med Chem. 2005 Apr 7;48(7):2325-35
references.pmid: 15801826
references.citation: J Comput Aided Mol Des. 2002 Jan;16(1):11-26
references.pmid: 12197663
references.citation: J Biol Chem. 1989 May 25;264(15):9030-8
references.pmid: 2656693