Dasatinib inhibitor selectivity

Dasatinib (Sprycel ) 12 inhibits Btk (IC50 = 5 nM) as well as the basal and lipopolysaccharide (LPS)-induced secretion of TNFa and IL-6 in U937 cells [65]. However, dasatinib s promiscuity [66] makes it difficult to ascribe these functional effects to direct Btk inhibition. The dasatinib-Btk(Y551E) crystal structure indicates binding to an active conformation, similar to that observed with Abl [43]. LFM-A13,13, was first described as a Btk inhibitor more than 10 years ago [67], although its poor Btk activity (IC50 = 2.5-17 /iM) and selectivity [68] require that caution be taken in interpreting functional effects. 

This dynamic multidrug-targeted prevention technique has been proposed in the treatment of chronic myeloid leukemia and the positive results obtained with the newly introduced drugs nilotinib and dasatinib suggested that a combination of two or three kinase inhibitors, when carefully selected to cover all known resistant mutations, could shut off all mechanisms of escape. 

Several inhibitors of their tyrosine kinase activity (non-selective from one receptor to the other) are approved for cancer therapy (imatinib, erlotinib, sorafenib and smitinib) and many others are clinically studied (dasatinib, nilotinib, pazopanib, vatalanib, vandetanib...). 

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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