Principles of Kinase Allosteric Inhibition and Pocket Validation

Abstract

With several marketed drugs, allosteric inhibition of kinases has translated to pharmacological effects and clinical benefits comparable to those from orthosteric inhibition. However, despite much effort over more than 20 years, the number of kinase targets associated with FDA-approved allosteric drugs is limited, suggesting the challenges in identifying and validating allosteric inhibitors. Here we review the principles of allosteric inhibition, summarize the discovery of allosteric MEK1/2 and BCR-ABL1 inhibitors, and discuss the approaches to screening and demonstrating the functional activity of allosteric pocket ligands.

Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib

“…Heretofore, all approved EGFR inhibitors target the orthosteric binding site either in a reversible (1,2) or irreversible manner (3, 4) (Figure 1). Non-ATP-competitive EGFR inhibitors holding the potential for superior selectivity profiles associated with favorable tolerability 17 were identified for the first time via screening in the presence/absence of high ATP concentrations in a pioneering publication by Jia et al in 2016. 18 These allosteric EGFR inhibitors (EGFRai) occupy a novel, allosteric binding site that exists in the presence of the activating L858R mutation.…”

It's ok to be outnumbered – sub-stoichiometric modulation of homomeric protein complexes

“…It is generally believed that allosteric binding sites do not face the same evolutionary pressure as orthosteric sites, resulting in higher diversity. 225 One can potentially take advantage of this diversity to achieve greater selectivity and this argument was made for the GPCR 226 and kinase 227 families. However, Abrusán's analysis of the PDB concluded that binding sites formed by more than one protomer in a homomeric complex are more similar across homologs than binding sites formed by a single protein or other complexes, suggesting that selectively targeting a certain protein over its homologs may be more challenging to achieve through this type of binding site.…”

2‐Phenylquinazolin‐4(3H)‐one scaffold as newly designed, synthesized VEGFR‐2 allosteric inhibitors with potent cytotoxicity through apoptosis

“…Therefore, the structural characteristics of the corresponding ligands are likewise variable due to the more heterogeneous structure of the residues in allosteric pockets. [ 2 ]…”

“…The target in the current study is VEGFR and thus, in the following part, light will be shed on this target owing to its vitality in angiogenesis and proliferation. [ 2,12,13 ] The back‐to‐front approach is exploited to discover new methylated oxazole derivatives X with moderate activity (IC 50 = 50 µM) as a promising type III inhibitor against VEGFR‐2. The designed ligand does not interact directly with the hinge region where the phenyl group is flanked by Phe1047 in the DFG loop, forming an π – π interaction; nitrogen of the oxazole ring forms a hydrogen bond with Asp1046 while 3‐hydroxymethyl‐phenyl is deeply occupied the hydrophobic pocket (Figure 3a,b).…”