Site-directed irreversible inhibitors of the erbB family of receptor tyrosine kinases as novel chemotherapeutic agents for cancer.
The erbB family of tyrosine kinases represents a versatile set of four plasma membrane receptors that possesses enormous diversity in signaling capability. The rationale to target this receptor system as an approach to cancer chemotherapy has continued to become more compelling with time. Both preclinical and clinical data strongly support the involvement of these receptors in the formation and progression of human cancers as well as establish a high correlation in cancer patients between receptor/ligand expression and poor prognosis. During the past 4 years significant progress has been made in the area of epidermal growth factor receptor tyrosine kinase inhibitors and new structural classes have emerged that exhibit enormous improvements with regard to potency, specificity, and in vitro and in vivo efficacy. More recent advancements in this field have resulted in the discovery of very specific, irreversible inhibitors of the erbB family that provide unique pharmacological properties and exceptional efficacy. The in vivo performance of these modern kinase inhibitors has improved to the point where several compounds are either in clinical trials or very near to that point in their development. This article will provide a brief biological review of the erbB family and the justification for targeting this receptor family in cancer therapeutics, and then highlight some of the more promising kinase antagonists with emphasis on irreversible inhibitors.
Fry
D W
DW
Department of Cancer Research, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48106, USA. david.fry@wl.com
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors