Playing vital roles in cellular physiology, protein kinases have turned out to be major drug targets implicated in many types of diseases such as cancer, diabetes, neurodegeneration, and inflammation . The majority of small-molecule kinase inhibitors approved clinically or those in the drug discovery pipeline are characterized as type I or type II inhibitors that target the ATP-binding pocket of kinases. Highly conserved ATP pockets show significant structural similarity, resulting in inhibition of selectivity challenges.
Unique allosteric kinase inhibitors target allosteric pockets of kinases rather than their ATP site. They are classified according to their binding site: type III inhibitors bind to the active kinase conformation in a pocket adjacent to the ATP site, whereas type IV inhibitors entirely bind away from the ATP site . Although type III and IV inhibitors would potentially face fewer issues with potency and/or selectivity than ATP-competitive kinase inhibitors, they remain far less common. Only two of the FDA-approved kinase inhibitors (trametinib and cobimetinib) would be considered type III, and no inhibitors that bind to the kinase catalytic domain would be considered type IV [1-3].
Potential allosteric enzyme inhibitors and modulators were selected for the Life Chemicals proprietary Screening Set of almost 1,000 novel drug-like screening compounds.
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Figure 1. Types of allosteric kinase inhibitors according to 
Based on published data [1-5], four types of possible allosteric kinase sites were determined:
- Myristoyl pocket
- Inhibitor binding mode that occupies part of allosteric binding pocket adjacent to the ATP-site
- PIF-pocket (regulatory site targeted)
- Pocket type I1/2 relatively allosteric regulators of kinases
All available PDB structures with kinase allosteric inhibitors and other open databases were analyzed. The Life Chemicals HTS Compound Collection was searched for allosteric inhibitor analogs that may bind to one of the kinase allosteric sites. The PAINS filter and our in-house developed toxicophore and undesired functionalities filters were also applied to the selection of potential small-molecule kinase inhibitors. The screening set has been evaluated to exclude simple reagents and trivial chemotypes. Around 1,000 potential not-ATP competitive kinase inhibitors were selected.
Figure 2. Potential allosteric binding sites in kinases according to 
- Roskoski R Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 2016;103:26–48.
- Yueh C, Rettenmaier J, Xia B, et al. Kinase Atlas: Druggability Analysis of Potential Allosteric Sites in Kinases. J Med Chem. 2019;62(14):6512-6524.
- Dong J, Lu W, Pan X, Su P, Shi Y, Wang J, Zhang J. Discovery of novel Bcr-Abl inhibitors targeting myristoyl pocket and ATP site. Bioorg Med Chem. 2014;22(24):6876-84.
- Xu X, Chen Y, Fu Q, Ni D, Zhang J, Li X, Lu S. The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1. J Enzyme Inhib Med Chem. 2019 Dec;34(1):361-374.
- Wu P., Clausen M. H., Nielsen T. E. Allosteric small-molecule kinase inhibitors. Pharmacol. Ther. 2015;156:59–68.
- Xiaoyun Lu, Jeff B. Smaill, Ke Ding. New Promise and Opportunities for Allosteric Kinase Inhibitors. Angew. Chem. Int. Ed.2020,59, 13764–13776. doi.org/10.1002/anie.20191452