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Issue 7, 2016
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Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

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Abstract

A highly specific and potent (7 nM cellular IC50) inhibitor of p38α kinase was identified directly from a 12.6 million membered DNA-encoded small molecule library. This was achieved using the high fidelity yoctoReactor technology (yR) for preparing the DNA-encoded library, and a homogeneous screening technique – the binder trap enrichment technology (BTE). Although structurally atypical to other kinase blockers, this inhibitor was found by X-ray crystallography to interact with the ATP binding site and provide strong distortion of the P-loop. Remarkably, it assumed an alternative binding mode as it lacks key features of known kinase inhibitors such as typical hinge binding motifs. Interestingly, the inhibitor bound assuming a canonical type-II (‘DFG-out’) binding mode by forming hinge hydrogen bonds with the backbone, showed excellent shape complementarity, and formed a number of specific polar interactions. Moreover, the crystal structure showed, that although buried in the p38α active site, the original DNA attachment point of the compound was accessible through a channel created by the distorted P-loop conformation. This study demonstrates the usability of DNA-encoded library technologies for identifying novel chemical matter with alternative binding modes to provide a good starting point for drug development.

Graphical abstract: Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

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Supplementary files

Article information


Submitted
29 Apr 2016
Accepted
21 Jun 2016
First published
22 Jun 2016

This article is Open Access

Med. Chem. Commun., 2016,7, 1332-1339
Article type
Research Article

Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

L. K. Petersen, P. Blakskjær, A. Chaikuad, A. B. Christensen, J. Dietvorst, J. Holmkvist, S. Knapp, M. Kořínek, L. K. Larsen, A. E. Pedersen, S. Röhm, F. A. Sløk and N. J. V. Hansen, Med. Chem. Commun., 2016, 7, 1332
DOI: 10.1039/C6MD00241B

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