Over the past decade, therapeutics that target subsets of the 518 human protein kinases have played a vital role in the fight
against cancer. Protein kinases are typically targeted at the adenosine triphosphate (ATP) binding cleft by type I and II inhibitors, however,
the high sequence and structural homology shared by protein kinases, especially at the ATP binding site, inherently leads to polypharmacology.
In order to discover or design truly selective protein kinase inhibitors as both pharmacological reagents and safer therapeutic
leads, new efforts are needed to target kinases outside the ATP cleft. Recent advances include the serendipitous discovery of type
III inhibitors that bind a site proximal to the ATP pocket as well as the truly allosteric type IV inhibitors that target protein kinases distal
to the substrate binding pocket. These new classes of inhibitors are often selective but usually display moderate affinities. In this review
we will discuss the different classes of inhibitors with an emphasis on bisubstrate and bivalent inhibitors (type V) that combine different
inhibitor classes. These inhibitors have the potential to couple the high affinity and potency of traditional active site targeted small molecule
inhibitors with the selectivity of inhibitors that target the protein kinase surface outside ATP cleft.
Keywords: Protein kinase, inhibitors, bivalent, bisubstrate, ATP cleft, protein substrate, tyrosine kinases, mutations, selectivity, free energy
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