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Review
. 2015 Jan 16;10(1):175-89.
doi: 10.1021/cb5008376. Epub 2014 Dec 23.

Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges

Affiliations
Review

Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges

Meghan E Breen et al. ACS Chem Biol. .

Abstract

Protein kinases are important mediators of cellular communication and attractive drug targets for many diseases. Although success has been achieved with developing ATP-competitive kinase inhibitors, the disadvantages of ATP-competitive inhibitors have led to increased interest in targeting sites outside of the ATP binding pocket. Kinase inhibitors with substrate-competitive, ATP-noncompetitive binding modes are promising due to the possibility of increased selectivity and better agreement between biochemical and in vitro potency. However, the difficulty of identifying these types of inhibitors has resulted in significantly fewer small molecule substrate phosphorylation site inhibitors being reported compared to ATP-competitive inhibitors. This review surveys reported substrate phosphorylation site inhibitors and methods that can be applied to the discovery of such inhibitors, including a discussion of the challenges inherent to these screening methods.

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Figures

Figure 1
Figure 1
Crystal structure of the catalytic domain of Lck (PDB 1QPC). Highlighted are the N-terminal lobe (green), the C-terminal lobe (light blue), the hinge region (orange), the phosphate binding loop (purple), the activation loop (dark blue), and the gatekeeper residue (red). ATP is shown in stick depiction within the ATP binding site.
Figure 2
Figure 2
Comparison of the ATP and substrate binding sites for (A) the tyrosine kinase IRK (PDB 1IR3) and (B) the serine/threonine kinase Akt (PBD 1O6K). ATP-competitive ligands are shown in green, and substrate-competitive ligands are shown in orange. The substrate binding site is less defined and more solvent exposed than the ATP binding site.
Chart 1
Chart 1. Chemical Structures of Erbstatin and Tyrphostins
Figure 3
Figure 3
Crystal structure of the inactive form of IRK (PDB 1IRK) with Tyr1162 shown in green and Tyr1158 shown in cyan. Tyr1162 occupies the same binding site as the tyrosine residue in a substrate peptide, shown in orange (overlaid from PDB 1IR3).
Chart 2
Chart 2. Chemical Structures of Piceatannol and Piceatannol Analogs
Chart 3
Chart 3. Chemical Structure of ON012380
Chart 4
Chart 4. Chemical Structures of KX-01, Hydroxynaphthalene Amide 2f, and Hydroxyindole Amide 2k
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Chart 5
Chart 5. Chemical Structures of Bisubstrate Probes for Competitive Binding Assays
Figure 4
Figure 4
Crystal structure of IRK bound to an ATP analog (green) and a peptidic substrate mimic (orange), with residues within 20 Å of the ATP binding site highlighted in cyan (PDB 1IR3). The substrate binding site is located within this 20 Å radius.
Chart 6
Chart 6. Chemical Structures of Paramagnetic Probes for NMR Screening

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