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Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals

Award Number: UG3AR083022
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals - Arsenicals cause rapid, severe and painful inflammatory and blistering responses in the skin. The available medical countermeasures against arsenical-induced toxicity are not effective due to toxicity and a low therapeutic index. Hence, there is a demand for the development of more effective and less toxic antidotes for arsenicals. Developing hybrid inhibitors of bromodomain-containing protein 4 (BRD4) which are responsible for the regulation of inflammatory genes, receptor-interacting protein kinase-3 (RIP3, or RIPK3), a central player in necroptosis, and interleukin-6 (IL-6) would be an effective and efficient treatment to attenuate arsenical-induced inflammation. We have identified three potent inhibitors, SRI-43887, SRI-47362 and SRI-47561 of BRD4, RIPK3 and IL6. For example, SRI-43887 exhibited significant activity in vivo against phenylarsine oxide (PAO) and arsenicals (Lewisite)-induced mice. Continued optimization of these compounds will lead to the identification of a potential preclinical candidate(s) for the treatment of cutaneous injuries associated with arsenicals. To achieve this goal, we will (i) utilize molecular modeling to design and synthesize analogs of these three lead compounds and test in vitro for BRD4, RIPK3 and IL6 inhibitory activity; (ii) evaluate select compounds for cytotoxicity and in vitro drug-like properties (solubility, metabolic stability, log D, permeability); (iii) determine the in vivo pharmacokinetic profile (bioavailability and half-life); and (iv) perform in vivo studies on select compounds against PAO and Lewisite to determine the efficacy of these compounds. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, biological assays, pharmacokinetics, molecular biology and drug development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$283,946 )
2026	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	4	7/16/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2026	2025	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/2/2026	NON-COMPETING CONTINUATION	-$805,446
2026	2025	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	3/26/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	3/3/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$521,500
2026	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	4	7/7/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$283,946

Issue Date FY: 2025 ( Subtotal = $805,446 )
2025	2025	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/27/2025	NON-COMPETING CONTINUATION	$805,446
														Subtotal = $805,446

Issue Date FY: 2024 ( Subtotal = $824,145 )
2024	2024	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/9/2024	NON-COMPETING CONTINUATION	$824,145
														Subtotal = $824,145

Issue Date FY: 2023 ( Subtotal = $835,063 )
2023	2023	SOUTHERN RESEARCH INSTITUTE	2000 9TH AVE S	BIRMINGHAM	AL	35205	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/30/2023	NEW	$835,063
														Subtotal = $835,063

Grand Total All Awards = $2,180,708

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Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals

Award Number: UG3AR083022

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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