Ekb569

Figure 7 Second-generation EGFR kinase inhibitors.

2002, and other countries rapidly followed. A recent Phase III trial in NSCLC using a continuous daily dose of 250 mg failed to achieve the primary endpoint (survival).

Erlotinib (28) is closely related to gefitinib; it is a reversible ATP-competitive inhibitor of the kinase (IC50 = 2 nM), inhibits EGF-driven cellular growth (IC50 = 0.1 mM), and is orally active in disease models at 10-100mgkg_ 1 daily doses.219 Phase I trials achieved target blood levels dosing at 100 mg day_ 1 or greater.220 The MTD is 150 mg, and a familiar pattern of toxicity including diarrhea and skin rash was seen. The human half-life is about 24 h (approximately 48 h for gefitinib), and some antitumor activity was observed in these trials. Recent data from a Phase III trial, dosing erlotinib at 150mgday _ 1, shows a statistically significant increase in life expectancy compared with controls in patients with NSCLC, and the drug has been approved in the USA for this condition.221

These two compounds have resulted in many other EGFR inhibitors progressing to clinical studies, including those having modifications to the basic quinazoline pharmacophore, such as the pyrimidopyrimidine BIBX 1382BS (29)222 and the pyrrolopyrimidine PKI-166 (30) (Figure 7).223 Of interest is CI-1033 (canertinib, 31),224 which differs from gefitinib and erlotinib in that it both binds irreversibly at the ATP site of the kinase and has activity at the erbB2 kinase through a similar mechanism. The acrylamide residue at the 6-position of the quinazoline is not a particularly good Michael acceptor, but in binding at the ATP site is brought into close contact with Cys773 of the EGFR (and Cys805 in the erbB2), and results in alkylation.225 This approach may have the advantage that less frequent dosing is required for inhibition of kinase function - for instance, 72 h after a single 40 mg kg _ 1 oral dose to mice there is still 75% inhibition of the EGFR kinase. However, the approach carries risks in that alkylated proteins can often cause in-host immune responses, which could limit further dosing. CI-1033 (31) has progressed to Phase II trials in patients and shown modest activity, but with more severe toxicity than was seen with the reversible agents. A second EGFR/erbB2 irreversible inhibitor built on the 3-cyanoquinoline pharmacophore EKB-569 (32)226 is in Phase II trials.

7.08.5.5.6 ErbB2 and cancer

A large amount of evidence is available that highlights the important role that the erbB2 RTK plays in mediating signaling by ligand-dependent activation of other erbB family members.227'228 While a natural ligand is unknown, this activation is achieved through heterodimerization with the other erbB family members.229 Overexpression of the kinase is transforming and tumorigenic.230 It is overexpressed in many other solid tumors,231 and the link with cancer is best characterized in breast cancer, where approximately 30% of tumors overexpress the kinase,232 and correlates with poor prognosis.

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7.08.5.5.7 Inhibitors of ErbB2

The only erbB2 inhibitor presently approved for treatment is a humanized inactivating monoclonal antibody, trastuzumab (Herceptin).233,234 It produces a 15% response rate in erbB2-overexpressing breast cancer as a

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