Gefitinib inhibitor selectivity

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]. 

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. 

The KINOMEscan selectivity scores for a selection of the marketed kinase inhibitors demonstrate the potential for the type II inhibitors imatinib 7, sorafenib 8 and lapatinib 10 to display higher selectivity than the type I inhibitors sunitinib 3 and dasatinib 4, especially when only higher affinity off-target interactions are considered (S(100 nM) scores). It can also be seen that, despite their potential to inhibit multiple kinase family members, it is possible to achieve good levels of selectivity with type I inhibitors ([Pg.83]

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