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; N. J. V. Hansen
Med. Chem. Commun., 2016, 7, 1332-1339
https://doi.org/10.1039/c6md00241b

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