X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor

TY - JOUR

T1 - X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor

AU - Elkins, Jonathan M.

AU - Wang, Jing

AU - Deng, Xianming

AU - Pattison, Michael J.

AU - Arthur, J. Simon C.

AU - Erazo, Tatiana

AU - Gomez, Nestor

AU - Lizcano, Jose M.

AU - Gray, Nathanael S.

AU - Knapp, Stefan

PY - 2013/6/13

Y1 - 2013/6/13

N2 - The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.

AB - The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.

KW - MEK5-ERK5 PATHWAY

KW - BREAST-CANCER

KW - PROSTATE-CANCER

KW - GROWTH-FACTOR

KW - TARGETED DELETION

KW - ACTIVATED PROTEIN-KINASE

KW - IDENTIFICATION

KW - BMK1/ERK5

KW - EXPRESSION

KW - SIGNALING PATHWAY

U2 - 10.1021/jm4000837

DO - 10.1021/jm4000837

M3 - Article

C2 - 23656407

SN - 0022-2623

VL - 56

SP - 4413

EP - 4421

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -