# Core 3: Drug Discovery and Development Core

> **NIH NIH U54** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $740,173

## Abstract

Cutaneous exposure to arsenicals causes vesicular skin lesions, blisters, and cutaneous inflammation, which
progresses to multi-organ tissue damage and death. Lewisite, diphenylchlorarsine, diphenylcyanoarsine and
diethylchloroarsine have been identified as potential threat chemicals by CounterACT (NIH) program for which
antidotes/agents are needed. Preliminary data indicate that epigenetic pathways that are bromodomain 4
(BRD4)-dependent are up-regulated in multiple organs following cutaneous exposure to arsenicals. In addition,
unfolded protein response (UPR) signaling is elevated under these conditions, which has been shown by the
investigators to be associated with inflammatory responses. Preliminary data has also shown that necrosis
regulators, such as receptor-interacting protein (RIP) kinases and the antioxidant, heme oxygenase-1 (HO-1),
could be additional potential targets. The overall goal of the Drug Discovery and Development Core (DDC) is to
collaborate with the investigators within the Research Center of Excellence in Arsenicals to identify and
prioritize novel molecular target-based approaches to develop countermeasures for mitigating the effects of skin
exposure to chemical vesicants. This will include the identification of novel small molecules that alleviate
cutaneous injury, pulmonary and renal toxicity and testing of these compounds in vivo. The approach proposed
herein will address the effective inhibition of several critical pathways and associated organ damage
simultaneously. The DDC has expertise in compound screening and assay development, involving novel and
diverse screening libraries which include over 4,000 FDA approved drugs. The core has a strong medicinal
chemistry component with extensive experience in lead optimization and drug discovery, including computational
and analytical chemistry and structural biology. Therefore, the major focus of these studies is on targeting novel
inhibitory compounds of BRD4 as potential antidotes of arsenicals. Given that some of these targets may have
tissue specificity (e.g., HO1 is critically associated with renal injury and is modulated in mice exposed to lewisite)
and simultaneous inhibition of multiple targets may provide a more effective approach, we will also identify
compounds affecting UPR, HO1 and RIP kinases. As compounds advance in in vitro and in vivo pharmacokinetic
studies, pharmaceutics/formulations and toxicology will be applied to the programs. These combined capabilities
provide the Center the ability to identify compounds suitable for IND-enabling studies. It will be the function of
the DDC to support the Center by identifying the hit compounds and ultimately developing novel leads and
potential clinically useful drugs with optimized biological and biophysical properties.

## Key facts

- **NIH application ID:** 10249111
- **Project number:** 5U54ES030246-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Mark J Suto
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $740,173
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249111

## Citation

> US National Institutes of Health, RePORTER application 10249111, Core 3: Drug Discovery and Development Core (5U54ES030246-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10249111. Licensed CC0.

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