Wednesday, July 2, 2025 7/2/2025

Targeting AbcA1 and Ldlr production for the Discoveryof Alzheimer's disease Drugs

Award Number: R16GM145547
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Targeting AbcA1 and Ldlr production for the Discoveryof Alzheimer's disease Drugs - Alzheimer’s disease is the most common incurable form of dementia affecting 50 million individuals worldwide. Apolipoprotein E4 (APOE4) is the strongest genetic risk factor that is directly linked to its pathogenesis. ApoE is a cholesterol- and lipid-carrier protein that has been implicated in Alzheimer’s disease, aging, and other neurological disorders. Isoform-dependent effect on amyloid accumulation and clearance have been found in humans and mice with APOE4 being detrimental. Haploinsufficiency of ApoE4 and possibly ApoE3 decreases amyloid pathology. Low Density Lipoprotein Receptor (LDLR) plays an important role in the endocytosis of ApoE proteins. LDLR overexpression has been found to decrease ApoE levels and inhibit amyloid formation. Additionally, ApoE’s role in lipidation influences Alzheimer’s pathogenesis. ATP-binding cassette transporter A1 (AbcA1) protein transfers cellular cholesterol onto extracellular lipid-poor apolipoproteins. Overexpression of ABCA1 gene has also been found to inhibit amyloid formation. Therefore, we set out to develop small organic molecules that can increase AbcA1 and/or Ldlr while decreasing ApoE protein levels. Such compounds would likely reduce and clear amyloid plaque deposition in affected brains and provide therapeutic benefit in Alzheimer’s disease. Five triarylmethyl amine (TAMA) small molecules emerged as first leads decreasing ApoE protein level (>30% reduction in the human astrocytoma brain cell line, analyzed using ELISA). The mechanism of action of the TAMA pharmacophore was via LXR antagonism. Structure-Activity Relationship (SAR) studies on the TAMA pharmacophore in five phases of focused libraries, identified five drug-like tertiaryl sulfonamides and aryl amines as new leads. They not only decreased ApoE levels in vitro, but also increased AbcA1/Ldlr protein levels validated by concentration-dependent studies. Three chiral leads in pure R/S forms had disproportionate effects on ApoE and AbcA1 raising the possibility of multiple targets. One of the 8 leads, compound 127 modulated the target proteins in the transgenic mice brains in preliminary in vivo studies. The successful in vivo efficacy of 127 validates its ability to pass the blood-brain barrier (BBB). Preliminary in vitro toxicological experiments revealed all the 8 lead compounds to be not toxic. The SuRE support will enable PI and his undergraduate/graduate research team to utilize the TAMA pharmacophore with critical appendages identified in newer and more potent sulfonamide leads to generate new and novel scaffolds-based leads. These scaffolds are expected to be lighter, drug-like, chemically and pharmacokinetically stable, and less lipophilic. PI aims at performing chemical synthesis and biological screening in his lab with the guidance of a committed consultant.


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 = $139,897 )
2025	2025	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	4	4/24/2025	NON-COMPETING CONTINUATION	$139,897
														Subtotal = $139,897

Issue Date FY: 2024 ( Subtotal = $239,471 )
2024	2024	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	3	3/20/2024	NON-COMPETING CONTINUATION	$125,524
2024	2024	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	001	3	6/18/2024	NON-COMPETING CONTINUATION	$13,947
2024	2024	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	002	3	7/22/2024	SUPPLEMENT FOR EXPANSION	$100,000
														Subtotal = $239,471

Issue Date FY: 2023 ( Subtotal = $239,327 )
2023	2023	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	001	2	9/5/2023	SUPPLEMENT FOR EXPANSION	$99,548
2023	2023	CALIFORNIA STATE UNIVERSITY, FRESNO	5150 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	2	3/27/2023	NON-COMPETING CONTINUATION	$139,779
														Subtotal = $239,327

Issue Date FY: 2022 ( Subtotal = $139,700 )
2022	2022	CALIFORNIA STATE UNIVERSITY, FRESNO	5241 N MAPLE AVE	FRESNO	CA	93740	FRESNO	USA	Biomedical Research and Research Training	000	1	4/22/2022	NEW	$139,700
														Subtotal = $139,700

Grand Total All Awards = $758,395

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Targeting AbcA1 and Ldlr production for the Discoveryof Alzheimer's disease Drugs

Award Number: R16GM145547

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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