Abstract
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
Current Pharmaceutical Design
Title:New Directions in Targeting Protein Kinases: Focusing Upon True Allosteric and Bivalent Inhibitors
Volume: 18 Issue: 20
Author(s): Vandana Lamba and Indraneel Ghosh
Affiliation:
Keywords: Protein kinase, inhibitors, bivalent, bisubstrate, ATP cleft, protein substrate, tyrosine kinases, mutations, selectivity, free energy
Abstract: 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.
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Cite this article as:
Lamba Vandana and Ghosh Indraneel, New Directions in Targeting Protein Kinases: Focusing Upon True Allosteric and Bivalent Inhibitors, Current Pharmaceutical Design 2012; 18 (20) . https://dx.doi.org/10.2174/138161212800672813
DOI https://dx.doi.org/10.2174/138161212800672813 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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