Cancer therapies targeted to the epidermal growth factor receptor and its family members

Abstract

This review will provide an overview of therapeutic strategies that are targeted to the epidermal growth factor receptor (EGFR) network of signal transduction, with a focus on EGFR itself and the closely related Her-2/neu/ erbB2 (erbB2) receptor. EGFR is the founding member of the erbB family of receptor tyrosine kinases, type I membrane spanning proteins that bind a variety of peptide growth factor ligands and initiate signal transduction along multiple downstream pathways towards proliferation, survival and angiogenesis. EGFR and erbB2 are validated targets for anticancer therapy and several such targeted therapeutic agents are already approved for use in patients. These include monoclonal antibodies directed to the extracellular domains of one or more erbB receptor and small molecule inhibitors of their intracellular tyrosine kinase domains. The advantages and disadvantages of these agents, as well as new and emerging agents in this class of targeted therapeutics, will be discussed. Recent progress towards understanding the molecular and pharmacodynamic causes of treatment failure or success will also be addressed. Finally, the therapeutic potential of targeted combinations, those directed at multiple facets of erbB-family signalling and those targeted to erbB and non-erbB receptor systems, will be reviewed.

Profile and Molecular Modeling of 3-(Indole-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole-2,5dione (1) as a Highly Selective VEGF-R2/3 Inhibitor

“…The PKs have been selected for the determination of an IC 50 profile of 1 because they are involved in malignant diseases and because they represent different PK families. As can be seen in Table , 1 is actually selective over the homologous TKs including EGF-R, ERbB2, TIE2, PDGFRβ, SRC, and FAK. , Compound 1 inhibited VEGF-R2/3 in the low nanomolar range, but compared to VEGF-R2, the kinases PDGFRβ inhibited in an almost 300-fold higher concentration (IC 50 = 6.8 × 10 -7 M), FAK (IC 50 = 9.7 × 10 -7 M) and the other PKs (EPHB4, IGF1-R, ABL1, INS-R, PLK1, CDK2/4, GSK3-β, NEK2, Aurora A/B 41 ) in only the micromolar range. In particular, the selectivity of 1 for VEGF-R2/3 over INS-R is important because a critical requirement for a PK inhibitor to be further developed is to avoid disturbing glucose homeostasis .…”

Polymer Carriers for Anticancer Drugs Targeted to EGF Receptor

“…To date, many monoclonal antibodies, tyrosine kinase inhibitors, and EGFR‐binding fragments have been identified and developed 9. These exogenous ligands can be exploited either as tumor‐targeting devices for classical chemotherapeutics or as competitive inhibitors of endogenous ligands that can directly inhibit cell differentiation and proliferation.…”