Structure- and Similarity-Based Survey of Allosteric Kinase Inhibitors, Activators, and Closely Related Compounds

Abstract

Allosteric kinase inhibitors are thought to have high selectivity and are prime candidates for kinase drug discovery. In addition, the exploration of allosteric mechanisms represents an attractive topic for basic research and drug design. Although the identification and characterization of allosteric kinase inhibitors is still far from being routine, X-ray structures of kinase complexes have been determined for a significant number of such inhibitors. On the basis of structural data, allosteric inhibitors can be confirmed. We report a comprehensive survey of allosteric kinase inhibitors and activators from publicly available X-ray structures, map their binding sites, and determine their distribution over binding pockets in kinases. In addition, we discuss structural features of these compounds and identify active structural analogues and highconfidence target annotations, indicating additional activities for a subset of allosteric inhibitors. This contribution aims to provide a detailed structure-based view of allosteric kinase inhibition.

Nanomolar, noncovalent antagonism of hedgehog cholesterolysis: exception to the “irreversibility rule” for protein autoprocessing inhibition

“…A single allosteric site that can toggle between activation and inhibition depending on the effector is intriguing and finds precedent in selected metabolic and signaling enzymes. 35,36 Despite descriptions of protein autoprocessing domains as primitive or proto-zymes, left over from an earlier age, we continue to find close parallels between their mechanisms and extant enzymes. Moreover, the notion that protein autoprocessing domains like HhC and inteins represent intractable targets for noncovalent inhibition should be discarded.…”

“Sandwich” Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients

“…EGFR TKI and EGFR mAbs both target EGFR; however, some of their mechanisms of action and their blocking effects do not completely overlap ( Figure 2 ). Low-molecular-weight TKIs block EGFR signaling by either competing with ATP ( 20 ) or changing the structure of EGFR (known as allosteric inhibition) ( 40 ). For high-molecular-weight mAbs, EGFR mAbs have the following mechanisms in addition to direct tumor inhibition by preventing ligand binding by blocking the ligand-binding extracellular domain.…”

Chemical Probes for Understudied Kinases: Challenges and Opportunities

“…216,217 Beyond the common type I and type II inhibitors, allosteric protein kinase inhibitors have become more attractive over time, providing distinct opportunities for the development of novel chemical probes and therapeutics. [218][219][220][221] Inhibitors targeting allosteric pockets adjacent to the ATP binding site have been classified as type III inhibitors while such targeting more distant allosteric sites are often referred to as type IV inhibitors. 222 It should be noted, however, that these classifications are not used consistently in the literature.…”