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Single molecules with multi-mechanistic modes of action as probative anti-Alzheimer’s agents

Award Number: SC3GM140980
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: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Single molecules with multi-mechanistic modes of action as probative anti-Alzheimer’s agents - Project Summary/Abstract Per 2019 Alzheimer’s report, Alzheimer’s disease (AD) dire statistics include: a current patient load of 5.8 million that is projected to expand to 14 million by 2050 in the US, increases in deaths by 145% (per 2000-2017 data), and climbing healthcare costs - $290 billion in 2019. In terms of pharmacotherapy, five clinical drugs [i.e., three cholinesterase inhibitors (ChEIs), one N-methyl-D-aspartate receptor antagonist (NMDRA), and one ChEI/NMDRA combo-drug] are indicated for AD and these drugs only provide symptomatic relief - they do not slow disease progression. A triad of poor health outcomes, lack of effective drugs, and high failure rates of pipeline molecules in clinical trials has therefore increased the urgency to discover more robust anti-AD molecules with novel mechanisms for slowing disease progression. The overall objective of this grant application is to 1) synthesize derivatives of Tubastatin A (a highly selective HDA6 inhibitor, IC50 = 15 nM), 2) evaluate each derivative for binding/functional activities at individual sigma (σ) receptors, and 3) determine each compound’s ability to inhibit histone deacetylase-6 (HDAC6). Central hypothesis: single molecules designed using the multi-target-directed ligands (MTDL) paradigm could more effectively mitigate AD’s neurodegenerative pathogenic cascades and repair cognitive deficits. Evidently, in AD animal models, independent σ-1 activation or σ-2 blockade or HDAC6 inhibition commonly result in decreased neurodegeneration and improved cognitive function. Therefore, our synthesized derivatives are expected to exhibit a de-novo σ-1/HDAC6 or σ- 2/HDAC6 combo-mechanistic anti-neurodegenerative approach towards slowing AD progression or potentially modifying the disease.


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: 2024 ( Subtotal = $99,264 )
2024	2024	UNIVERSITY OF THE INCARNATE WORD	4301 BROADWAY	SAN ANTONIO	TX	78209	BEXAR	USA	Biomedical Research and Research Training	000	4	6/18/2024	NON-COMPETING CONTINUATION	$99,264
														Subtotal = $99,264

Issue Date FY: 2023 ( Subtotal = $101,928 )
2023	2023	UNIVERSITY OF THE INCARNATE WORD	4301 BROADWAY	SAN ANTONIO	TX	78209	BEXAR	USA	Biomedical Research and Research Training	001	3	6/16/2023	NON-COMPETING CONTINUATION	$99,264
2023	2022	UNIVERSITY OF THE INCARNATE WORD	4301 BROADWAY	SAN ANTONIO	TX	78209	BEXAR	USA	Biomedical Research and Research Training	000	2	5/26/2023	NON-COMPETING CONTINUATION	$2,664
														Subtotal = $101,928

Issue Date FY: 2022 ( Subtotal = $96,600 )
2022	2022	UNIVERSITY OF THE INCARNATE WORD	4301 BROADWAY	SAN ANTONIO	TX	78209	BEXAR	USA	Biomedical Research and Research Training	000	2	6/7/2022	NON-COMPETING CONTINUATION	$96,600
														Subtotal = $96,600

Issue Date FY: 2021 ( Subtotal = $96,600 )
2021	2021	UNIVERSITY OF THE INCARNATE WORD	4301 BROADWAY	SAN ANTONIO	TX	78209	BEXAR	USA	Biomedical Research and Research Training	000	1	6/15/2021	NEW	$96,600
														Subtotal = $96,600

Grand Total All Awards = $394,392

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Single molecules with multi-mechanistic modes of action as probative anti-Alzheimer’s agents

Award Number: SC3GM140980

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: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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