Small Molecule Tyrosine Kinase Inhibitors

Tyrosine kinase activity is required for EGFR-mediated tumorigenicity. Overexpression of protein tyrosine kinase receptors correlates with a poor prognosis and a shorter survival time in patients with breast cancer. Recent research has focused on therapies that ablate this function.

Quinazoline compounds represent a class of competitive inhibitors of the ATP-binding site that are orally active, potent, and selective tyrosine kinase inhibitors (59). These small molecule tyrosine kinase inhibitors competitively block the ATP-binding site on the receptor and subsequently prevent signal transduction. These agents also target the highly tumorigenic EGFR mutant vIII that may be inaccessible to monoclonal antibodies.

In breast cancer, several tyrosine kinase inhibitors are being investigated. These include gefitinib (Iressa®; AstraZeneca Pharmaceuticals, Wilmington, Delaware, U.S.A.), erlotinib (Tarceva®; Genentech Inc., South San Francisco, California, U.S.A.), lapatinib (Tykerb®; GlaxoSmithKline, Research Triangle Park, North Carolina, U.S.A.), and CI-1033 (Pfizer, New York, U.S.A.). The principle differences among these tyrosine kinase inhibitors are that gefitinib and erlotinib are specific for the ErbB-1, and are reversible inhibitors; whereas lapatinib is a reversible dual inhibitor that targets ErbBl and ErbB2. CI-1033 is an irreversible inhibitor that blocks a region of the catalytic site conserved among all ErbB receptors and is referred to as a Pan-Erb inhibitor.

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