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

TY - JOUR

T1 - Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library

AU - Petersen, L. K.

AU - Blakskjær, P.

AU - Chaikuad, A.

AU - Christensen, A. B.

AU - Dietvorst, J.

AU - Holmkvist, J.

AU - Knapp, S.

AU - Kořínek, M.

AU - Larsen, L. K.

AU - Pedersen, A. E.

AU - Röhm, S.

AU - Sløk, F. A.

AU - Hansen, N. J V

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1039/c6md00241b

DO - 10.1039/c6md00241b

M3 - Journal article

AN - SCOPUS:84978909845

SN - 2040-2503

VL - 7

SP - 1332

EP - 1339

JO - MedChemComm

JF - MedChemComm

ER -