`
`. Tyrosine Kinase Inhibitors Against
`EGF Receptor-Positive Malignancies
`
`Elise A. Sudbeck, Sutapa Ghosh, Xlng-Ping Liu,
`Yaguo Zheng, Dorothea E. Myers, and Faith. M. Uckun
`
`1 . Introduction
`
`' The role of protein tyrosine kinases (P'I‘Ks) in the survival of cancer cells
`and their potential use in anticancer therapy has led to their selection as anti-
`cancer drug targets. Tyrosine lcinases which are being studied for this purpose
`include epidermal growth factor receptor (EGFR) (1-6), Janus kinases (JAKs)
`(7-13), Bruton’s tyrosine lcinase (BTK) (14-16), platelet-derived g_ro_wth fac~
`tor (PDGF) (17), protein kinase C (PKC) (18-24), Lck (25.26), Trk (27-30),
`and others. The strategies used to attenuate or disable kinases implicated in
`cancer include the use of anfibodies, immunoconjugates, ligand-binding cyto-
`toxic agents, and small-molecule inhibitors. Each of these strategies has shown .
`some promise for the treatmefit of cancer. I-Ierceptin (31-35), for example, is
`an immunotherapeutic agent that binds to the extracellular domain of HER2
`(also referred to as ErbB-2, a tyrosine kinase belonging to the same family as
`EGFR) at nanomolar levels. EGF-genistein (EGF-gen)‘ is an EGFR—binding
`cytotoxic agent that also shows potency in the nanomolar range (2,36) and will
`be discussed in this chapter. The search for new small molecules that inhibit
`kinases has involved traditional approaches, including the testing of natural
`products, random screening of chemical libraries, the use of classical struc-
`ture-activity relationship studies, and the incorporation of structure—based drug
`
`design approaches and"combinatorial chemistry techniques. As a result, sev-
`years thatmayproveusefulaspotentnewanticancerdrugs.
`
`eral promising small-molecule inhibitors have also been identified in recent
`
`Small-molecule inhibitors of kinases that show promise as anticancer agents
`include inhibitors of EGFR. EGF exerts pleiotropic biologic effects by binding
`
`From: Methods In Molecular Biology, vol. 166: Immunotoxln Methods and Protocols
`Edited by: W. A. Hall 0 Humana Press Inc., Totowa. NJ
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