ErbB selective inhibitors

Selective Inhibitors Targeting Individual ErbB Family Members. 96... 

The opposite case, of over-selecting a patient population, has also been seen recently, and with another ERBB 1 inhibitor— the monoclonal antibody cetuximab. Initial studies were conducted in patients whose tumors had immunohistochemical evidence of EGER expression (25). This ultimately led to inclusion of this criterion in the drug label. It was subsequently found that benefit from cetuximab may also occur in the absence of ERBBl expression (26). 

ErbB inhibitors in development differ in several aspects, including potency, selectivity, and mechanism of inhibition. Fortunately, there are data that compare erlotinib, gefitinib, lapatinib, canertinib, HKI-272, and BIBW 2992 directly in enzymatic and cellular studies, as shown in Tables 2 and 3 [89,95]. 

Singh J, Dobrusin EM, Fry DW et al. Structure-based design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB receptor subfamily of protein tyrosine kinases. J Med Chem 1997 40 1130-1135. 

Iressa (gefitinib, 2) is a reversible inhibitor, thus mechanistically it is possible to excert less toxicity in comparison to similar irreversible inhibitors, which bond to the protein covalently. Gefitinib (2) is also quite selective. It is at least 100-fold selective against other tyrosine kinases such as erbB-2, KDR, c-flt or serine/threonine kinases such as PKC, MEK-1, and ERK-2. 

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