NON-CATALYTIC SUBSTRATE-SELECTIVE P38alpha-SPECIFIC MAPK INHIBITORS WITH ENDOTHELIAL-STABILIZING AND ANTI-INFLAMMATORY ACTIVITY, AND METHODS OF USE THEREOF

a technology of p38alpha-specific mapk inhibitors and substrates, which is applied in the field of compounds to achieve the effects of stabilizing the endothelial or epithelial barrier function, reducing inflammation, and reducing lps-induced lung injury

Inactive Publication Date: 2019-05-23
U S GOVERNMENT REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]In one embodiment, the compound selectively inhibits p38α MAPK. In some embodiments, inhibition of p38α MAPK does not result in loss of a p38α-dependent counterregulatory response. In one embodiment, the p38α-dependent counterregulatory response relates to mitogen- and stress-activated protein kinase-1 (MSK1), or MSK2. In some embodiments, inhibiting p38α MAPK stabilizes an endothelial or epithelial barrier function. In other embodiments, inhibiting p38α MAPK reduces inflammation. In some embodiments, inhibiting p38α MAPK mitigates LPS-induced lung injury. In other embodiments, inhibiting p38α MAPK regulates leukocyte trafficking. In one embodiment, inhibiting p38α MAPK regulates cytokine expression.

Problems solved by technology

p38 Mitogen-Activated Protein Kinases (MAPKs), contribute to pathogenesis of many diseases, but the currently available p38 catalytic inhibitors (e.g., SB203580) are poorly effective and cause toxicity possibly due to activity against non-inflammatory p38 isoforms (e.g., p38β) and loss of p38α-dependent counterregulatory responses (e.g., MSK1 / 2).

Method used

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  • NON-CATALYTIC SUBSTRATE-SELECTIVE P38alpha-SPECIFIC MAPK INHIBITORS WITH ENDOTHELIAL-STABILIZING AND ANTI-INFLAMMATORY ACTIVITY, AND METHODS OF USE THEREOF
  • NON-CATALYTIC SUBSTRATE-SELECTIVE P38alpha-SPECIFIC MAPK INHIBITORS WITH ENDOTHELIAL-STABILIZING AND ANTI-INFLAMMATORY ACTIVITY, AND METHODS OF USE THEREOF
  • NON-CATALYTIC SUBSTRATE-SELECTIVE P38alpha-SPECIFIC MAPK INHIBITORS WITH ENDOTHELIAL-STABILIZING AND ANTI-INFLAMMATORY ACTIVITY, AND METHODS OF USE THEREOF

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Experimental program
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example 1

ling of p38 MAPK Substrate-Docking Site, Compound Identification, and Screening Compounds for Direct, Selective Interaction with p38α

[0260]The inhibitors and methods of the invention relate to a CADD-based strategy to identify low molecular weight compounds predicted to bind near the ED substrate-docking site of mouse unphosphorylated p38α (MAPK14 variant-1; PDB:1P38), which is >99% identical with human p38α (variant-2) (FIG. 1a). The ED and CD sites in p38α are located at either end of a substrate-binding cleft located on the opposite side of the protein from the catalytic site (FIG. 1a). A pocket near the ED binding site comprising 10 amino acids, only 7 of which were identical in p38α and p38β, was identified (FIG. 1b). Overlay of structures of mouse unphosphorylated (PDB:1P38) and dual-phosphorylated p38α (PDB:3PY3) revealed near-superimposition of the targeted pocket in the two forms (FIG. 1c).

[0261]An overview of the CADD screening and compound testing protocols is shown in FI...

example 2

f Compounds on Endothelial Barrier Functions

[0264]The capacity of UM60 and UM101 to stabilize endothelial barriers to macromolecules and neutrophils in TNFα- and hyperthermia-stressed HMVECL monolayers was tested (FIG. 2). Combined exposure to 1 ng / ml TNFα and hyperthermia (39.5° C.) for 6 h increased permeability for 10 kDa dextran 2.8-fold, compared with untreated 37° C. cells. Pretreating with 10 μM SB203580 for 30 min reduced TNFα / hyperthermia-induced permeability by 50% (FIG. 2a). Pretreatment with UM60 at 10 and 25 μM had no effect on permeability, but 100 μM UM60 reduced the TNFα / hyperthermia-induced permeability increase by 71% while UM101 at 10, 25, and 100 μM reduced the TNFα / hyperthermia-induced permeability increase by 74%, 89% and >100%, respectively.

[0265]Preincubating HMVECLs at 39.5° C. for 6 h increased subsequent IL-8-directed neutrophil TEM from 22.8±0.45×103 to 31.8±0.54×103 neutrophils (FIG. 2b). Pretreatment with 10 μM SB203580 reduced hyperthermia-augmented ne...

example 3

Effectiveness of SB203580 and UM101 in Mouse ALI

[0266]The effectiveness of UM60, UM101, and SB203580 in mitigating transalveolar protein and neutrophil extravasation in a mouse model of LPS / hyperthermia-induced ALI was compared (FIG. 2c and FIG. 2d). Mice received a single intraperitoneal injection of 100, 300, 500, or 1000 μg UM101, 1000 μg UM60, or 1000 μg SB203580 in 0.5 ml 2% DMSO 30 min prior to intratracheal instillation of 50 μg LPS and transfer to hyperthermic chambers. Control mice received DMSO. Four of six UM60-treated, one of six SB203580-treated, and one of eleven DMSO-treated control mice died within 24 h. All sixteen UM101-pretreated mice survived. Lung lavage from DMSO-pretreated, LPS / hyperthermia-challenged mice contained 1.09±0.19 mg / ml protein and 3.97±1.07×106 neutrophils. Compared with DMSO-treated controls, lavage protein concentration and neutrophil content in mice pretreated with 1000 μg SB203580 were reduced by 42% and 46.8%, respectively. Lavage protein con...

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Abstract

Compounds that inhibit p38α MAPK protein, and methods of using the same, are provided for treating or preventing diseases such as cancer or inflammatory diseases.

Description

RELATED APPLICATIONS[0001]This application claims priority to, and the benefit of, U.S. Provisional Application No. 62 / 353,856, filed Jun. 23, 2016, and U.S. Provisional Application No. 62 / 469,913, filed Mar. 10, 2017. The contents of each of these applications are incorporated herein by reference in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under Grant Nos. CA120215 and HL069057 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The invention relates generally to compounds that are inhibitors of p38 Mitogen-Activated Protein Kinases (MAPKs) proteins, and more particularly, but not exclusively, to compounds that inhibit p38α MAPK protein by binding to a pocket near the ED substrate-docking site of p38α MAPK, and methods of using such compounds as treatments for disease.BACKGROUND OF THE INVENTION[0004]p38 Mitogen-Activated Protein Kinas...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5375A61K31/54A61K31/18A61P29/00A61P35/00
CPCA61K31/5375A61K31/54A61K31/18A61P29/00A61P35/00A61P31/00A61P19/02C07D295/073C07D263/32C07D413/12C07D213/81
Inventor SHAPIRO, PAUL S.MACKERELL, JR., ALEXANDER D.HASDAY, JEFFREY D.
Owner U S GOVERNMENT REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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