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Development of novel NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease

Award Number: U01AG076481
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Development of novel NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease - Neuroinflammation has been recognized as an essential player in the pathogenesis of Alzheimer’s disease (AD). Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multimeric protein complex that tightly regulates the innate immune responses, has been suggested with critical roles in AD development and progression. Dysregulation of the NLRP3 inflammasome is responsible for the over production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses and cell death. Thus, NLRP3 inflammasome represents an attractive drug target for AD and offers promise to provide effective disease modifying potential. Over the past several years, our team has successfully developed novel small molecule NLRP3 inflammasome selective inhibitors (NSIs). We originally reported NSIs with sulfonamide containing chemical scaffolds, and have established a small molecule library containing > 200 compounds with various biological characteristics. Proof of concept studies of our 1st generation lead NSI in transgenic AD mouse models demonstrated target engagement and in vivo efficacy to reduce neuroinflammation and improve cognitive functions. Our recent medicinal chemistry campaign led to the identification of new lead NSIs with significantly improved potency and binding affinity. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization. The central hypothesis of this proposal is that structural optimization of the current two preclinical lead NSIs will be achieved by designing new viable analogs and isolating potent and orally available NSIs with improved pharmacokinetic (PK) properties (Aim 1), and that pharmacological suppression of the NLRP3 inflammasome by our NSIs will mitigate neuroinflammation and improve cognitive functions in preclinical AD animal models (Aim 2), which will be further evaluated by preclinical Investigational New Drug (IND)-enabling studies (Aim 3) to advance to clinical studies. For our hypothesis, the goal of this application is to accomplish preclinical IND-enabling studies on at least one candidate NSI and prepare for a meeting with the FDA and subsequent IND filing. Three aims are proposed to achieve our objectives. In Aim 1, new analogs of the lead NSIs will be designed, synthesized and biologically characterized to build a dynamic drug discovery and development pipeline. In Aim 2, selected NSIs from aim 1 will be tested for PK/PD properties in various animal models including AD mouse models. In aim 3, the top candidate NSI identified from Aim 2 will be subjected to IND-enabling studies including GMP production, GLP toxicology studies in rodents and dogs, and oral formulation development to prepare for IND filing and clinical trials. The proposed research is highly significant because we are developing a novel class of NSIs that will offer great promise to provide novel and effective therapeutics for AD, a devastating neurodegenerative disorder without cure currently.


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: 2025 ( Subtotal = $1,482,927 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	001	4	5/28/2025	NON-COMPETING CONTINUATION	$1,482,927
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	000	3	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,482,927

Issue Date FY: 2024 ( Subtotal = $1,403,321 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$1,403,321
2024	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	000	2	4/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,403,321

Issue Date FY: 2023 ( Subtotal = $1,653,222 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	000	1	4/6/2023	SUPPLEMENT FOR EXPANSION	$249,901
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	001	2	6/9/2023	NON-COMPETING CONTINUATION	$1,403,321
														Subtotal = $1,653,222

Issue Date FY: 2022 ( Subtotal = $1,426,573 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Aging Research	000	1	5/31/2022	NEW	$1,426,573
														Subtotal = $1,426,573

Grand Total All Awards = $5,966,043

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Development of novel NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease

Award Number: U01AG076481

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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