Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors

González-Medina, Mariana; Miljković, Filip; Haase, Gernot S.; Drueckes, Peter; Trappe, Joerg; Laufer, Stefan; Bajorath, Jürgen

doi:10.1016/j.ejmech.2019.112004

Cited by 3 publications

(1 citation statement)

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“…Even taking activity data incompleteness into account (i.e., not all inhibitors have been tested against the entire kinome), promiscuity of ATP-site-directed kinase inhibitors cannot be generalized. This is also consistent with results of selectivity-oriented kinase profiling − and increasing insights into the varying influence of kinase inhibition kinetics , and the dynamics of active versus inactive conformational states adapted by kinases …”

Section: Introductionsupporting

confidence: 87%

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

Laufkötter

Miljković

et al. 2021

J. Med. Chem.

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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.

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