Protein Kinases

Protein Kinases

Protein kinase inhibitors are an important class of drugs. The FDA has approved over 70 small molecules with this type of action [1, 2]. Approved kinase inhibitors are used in the treatment of a wide range of diseases from cancer to glaucoma [1]. Almost all protein kinases have a similar three-dimensional structure and consist of N- and C-lobes and an activation segment. A more detailed discussion of the kinases’ structure can be found in the excellent review by Roskoski [2]. The activation segment of all protein kinases begins with DFG, and almost all activation segments end with APE. This structural motif is about 35–40 residues long and is a key regulatory element of kinase function. Its position in the "on" or "off" state in many cases determines the mode of binding of the kinase inhibitor.

According to the classification proposed by Roskoski [3], kinase inhibitors can be divided into the following types:

  • Type I – binds in the ATP binding pocket. Enzyme is in ac active state (DFG-Din).
  • Type II – binds to the kinase in the inactive state (DFG-Dout). Subcategories:

◦         Type IIA – extend into the back cleft

◦         Type IIB – does not extend into the back cleft

  • Type III – allosteric inhibitors bound next to the ATP binding site
  • Type IV – allosteric inhibitors bound away from the ATP binding site
  • Type V – Bivalent inhibitor bound in the two kinase domains
  • Type VI – covalent inhibitors which bind irreversibly

The critical role of kinase selectivity for more effective treatments is widely appreciated. This could provide a new incentive for the search for new inhibitors for already validated targets over the years to come. To help you in this matter, there are a number of libraries of potential kinase inhibitors supposed to act as Types I-IV available in our inventory:

refs

1. Ayala-Aguilera CC, Valero T, Lorente-Macías Á, Baillache DJ, Croke S, Unciti-Broceta A. Small Molecule Kinase Inhibitor Drugs (1995-2021): Medical Indication, Pharmacology, and Synthesis. J Med Chem. 2021 Oct 8. doi: 10.1021/acs.jmedchem.1c00963. Epub ahead of print. PMID: 34624192.

2. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update. Pharmacol Res. 2021 Mar;165:105463. doi: 10.1016/j.phrs.2021.105463. Epub 2021 Jan 26. PMID: 33513356.

3. Roskoski R Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016 Jan;103:26-48. doi: 10.1016/j.phrs.2015.10.021. Epub 2015 Oct 31. PMID: 26529477.

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