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

> **NIH NIH SC3** · UNIVERSITY OF THE INCARNATE WORD · 2021 · $96,600

## Abstract

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.

## Key facts

- **NIH application ID:** 10172742
- **Project number:** 1SC3GM140980-01
- **Recipient organization:** UNIVERSITY OF THE INCARNATE WORD
- **Principal Investigator:** Donald M Sikazwe
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $96,600
- **Award type:** 1
- **Project period:** 2021-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172742

## Citation

> US National Institutes of Health, RePORTER application 10172742, Single molecules with multi-mechanistic modes of action as probative anti-Alzheimer’s agents (1SC3GM140980-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10172742. Licensed CC0.

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