# Design of Novel Non-catalytic Substrate-Selective p38 MAPK Inhibitor to Treat ARDS

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

Acute Respiratory Distress Syndrome (ARDS) is a complication of serious infections and trauma and an
important source of morbidity and mortality in Veterans and the general population. Despite improvements
in supportive care, no pharmaceutical therapies have been developed and mortality remains over 40%.
Although preclinical studies support pharmacologic inhibition of p38 mitogen-activated protein kinase
(MAPK) to treat a range of inflammatory diseases, including ARDS, the currently available p38 inhibitors
have had limited success in clinical trials due to toxicity and poor efficacy. Since these agents are catalytic
site inhibitors, they block all p38 activity. Most of these inhibitors target multiple p38 isoforms, even though
p38α is the only isoform required for inflammatory responses and other isoforms can be cytoprotective.
Furthermore, since p38α itself also regulates anti-inflammatory and counterregulatory genes via Mitogen-
and Stress-activated Protein Kinase (MSK)-1/2, we believe that targeting the catalytic site is an intrinsical-
ly flawed strategy.
We used computer-aided drug design (CADD) to identify novel small molecules that target the glutamate-
aspartate (ED) substrate docking site, which is required for phosphorylation of MAPK-activated protein
kinase-2 (MK2), a p38α substrate known to mediate inflammation, endothelial barrier function, and
leukocyte mobility; whereas MSK1/2 binds to the c o m m o n d o c k i n g ( CD) site. Using this strategy, we
identified p38α-binding compounds, including a lead compound, UM101, which selectively binds the
CADD-targeted pocket in p38α, but not p38β. UM101 stabilizes human lung microvascular endothelial
(HMVECL) barrier function, and inhibits LPS-induced proinflammatory gene expression in THP1 cells.
UM101 is also well-tolerated and more potent than the prototypical p38 catalytic inhibitor, SB203580, in
mitigating LPS-induced lung inflammation and permeability pulmonary edema in mice. RNASeq and
Ingenuity Pathway Analysis showed that UM101 inhibited only some SB203580-inhibitable genes, but
spared others including MSK1/2-dependent anti-inflammatory genes. Preliminary phosphopeptide analysis
failed to identify off-target effects. Three additional compounds were identified from the CADD search,
which share p38a-binding and biological activity with UM101.
Our central hypothesis is that targeting small molecules to p38α substrate docking sites rather than the
catalytic site will generate a spectrum of potential drugs with unique biological effects and reduced toxicity
profiles, which will be more effective in treating inflammatory diseases. The objectives of this proposal are
to: identify additional lead compounds with improved anti-inflammatory and endothelial barrier stabilizing
activity, analyze their function and mechanism of action, and analyze toxicity and efficacy of at least three
lead compounds as pre- and post-treatment in a mouse LPS-induced acute lung injury model. We will
identify ad...

## Key facts

- **NIH application ID:** 9932276
- **Project number:** 5I01BX004270-03
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** JEFFREY D HASDAY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932276

## Citation

> US National Institutes of Health, RePORTER application 9932276, Design of Novel Non-catalytic Substrate-Selective p38 MAPK Inhibitor to Treat ARDS (5I01BX004270-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932276. Licensed CC0.

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