Title: First comprehensive structural and biophysical analysis of MAPK13 inhibitors targeting DFG-in and DFG-out binding modes

Abstract

Background: P38 MAP kinases are centrally involved in mediating extracellular signaling in various diseases. While much attention has previously been focused on the ubiquitously expressed family member MAPK14 (p38α), recent studies indicate that family members such as MAPK13 (p38δ) display a more selective cellular and tissue expression and might therefore represent a specific kinase to target in certain diseases. Methods: To facilitate the design of potent and specific inhibitors, we present in this paper the structural, biophysical, and functional characterization of two new MAPK13-inhibitor complexes, as well as the first comprehensive structural, biophysical, and functional analysis of MAPK13 complexes with four different inhibitor compounds of greatly varying potency. Results: These inhibitors display IC₅₀ values either in the nanomolar range or micromolar range (> 800-fold range). The nanomolar inhibitors exhibit much longer ligand-enzyme complex half-lives compared to the micromolar inhibitors as measured by biolayer interferometry. Crystal structures of the MAPK13 inhibitor complexes reveal that the nanomolar inhibitors engage MAPK13 in the DFG-out binding mode, while the micromolar inhibitors are in the DFG-in mode. Detailed structural and computational docking analyses suggest that this difference in binding mode engagement is driven by conformational restraints imposed by the chemical structure of the inhibitors, andmore » may be fortified by an additional hydrogen bond to MAPK13 in the nanomolar inhibitors. Conclusions: These studies provide a structural basis for understanding the differences in potency exhibited by these inhibitors. General significance: They also provide the groundwork for future studies to improve specificity, potency, pharmacodynamics, and pharmacokinetic properties.« less

Authors:

Yurtsever, Zeynep ^[1]; Patel, Dhara A. ^[1]; Kober, Daniel L. ^[1]; Su, Alvin ^[1]; Miller, Chantel A. ^[1]; Romero, Arthur G. ^[1]; Holtzman, Michael J. ^[1]; Brett, Tom J. ^[1]

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+ Show Author Affiliations

1. Washington Univ. School of Medicine, St. Louis, MO (United States)

Publication Date:

Wed Jun 29 00:00:00 EDT 2016

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Org.:

USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); American Heart Association (AHA)

OSTI Identifier:

1329425

Alternate Identifier(s):

OSTI ID: 1396466

Grant/Contract Number:  

T32-GM007067; AC02-06CH11357; AC02-05CH11231

Resource Type:

Accepted Manuscript

Journal Name:

Biochimica et Biophysica Acta - General Subjects

Additional Journal Information:

Journal Volume: 1860; Journal Issue: 11; Journal ID: ISSN 0304-4165

Publisher:

Elsevier

Country of Publication:

United States

Language:

ENGLISH

Subject:

59 BASIC BIOLOGICAL SCIENCES; p38 kinase; Structure-based drug design; Chronic inflammatory lung disease; Kinase inhibitor; Inhibitor half-lives; Differential scanning fluorimetry