Sorafenib inhibitor selectivity

As well as its effect on the translation of inhibitory potency against the intended target to cellular activity, the complex whole-cell situation can have a profound effect on the observed selectivity of kinase inhibitors. A small selection of data for the type II inhibitor sorafenib 8 demonstrates the potential for selectivity profiles to be different when comparing isolated enzyme or whole cell data, showing it to be a more potent inhibitor of Flt-3 relative to VEGFR-2, PDGFR-p and c-Kit in cells than would be predicted from its kinase inhibitory profile (Table 3.2).23 Probing the mechanistic basis for cellular kinase inhibitor selectivity, researchers at the University of California demonstrated that differential pathway sensitivity could lead to selective effects in cells.24... 

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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