# Immunoproteasome inhibitors for the treatment of Alzheimer’s disease

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2022 · $616,032

## Abstract

Project Summary
With the failure of nearly all clinical trials for AD drugs in the pipeline to date, identification of a new class of drug
candidates has become imperative to bring about effective AD therapies. A major obstacle is the lack of
promising new drug targets unrelated to the events leading to the accumulation of the amyloid-beta (Aβ) and tau-
protein. We recently reported that linear peptide epoxyketones targeting the immunoproteasome (iP), an
inducible variant of the 20S constitutive proteasome (cP), may represent a new class of AD drugs that can
ameliorate cognitive deficits, independently of Aβ or tau accumulation. While displaying promising efficacy,
however, the prospect of these linear peptide epoxyketones for clinical use in AD appears limited at this time,
due to potential issues of having a poor brain accessibility, in vivo metabolic instability, and short circulation time
(largely attributable to the ABCB1-mediated drug efflux at the BBB and enzymatic hydrolysis by peptidases and
epoxide hydrolases). Yet, the family of peptide epoxyketones (‘short peptides with C-terminal α′,β′-epoxyketone
warhead’) remain attractive drug candidates considering their pharmacological advantages conferred by their
proven target specificity for the proteasomes and long-term safety in the clinic.
Our current findings reveal that some of the peptide epoxyketone family members containing a macrocycle have
the ability to resist the ABCB1-mediated efflux and metabolic stability superior to their linear counterparts, and
the potential to be a meaningful new treatment for patients with AD. Our objective in this application is to identify
and characterize one of these macrocyclic compounds best suited for brain iP inhibition in vivo and proceed to
the next phase of drug development. To do this, in aim 1 we will prepare the current sets of promising macrocyclic
peptide epoxyketones with different structural features that displayed comparable target inhibition and biological
activity in vitro and in cellulo on a gram scale. In aim 2, we will characterize in vivo properties of each macrocyclic
peptide epoxyketone to identify a lead drug candidate. In aim 3, we will verify in vivo efficacy and the proposed
mechanism of action of the lead drug candidate [iP inhibition → (NLRP3 inflammasome) → suppression of
microglial IL-1α release → blockade of astrocytes transformation (to A1 subtype) → neuronal survival] using two
mouse models of AD (APP/PS1 and PS19 tau transgenic mice). By completing the proposed study, we will have
identified a lead candidate with the best attributes for IND enabling studies and novel mode of action. These
results are expected to have an important positive impact by examining the validity of the previously untapped
iP-targeting approach for AD therapy and potentially offering a new direction for AD drug discovery.

## Key facts

- **NIH application ID:** 10458764
- **Project number:** 5R01AG073122-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Kyung Bo Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $616,032
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458764

## Citation

> US National Institutes of Health, RePORTER application 10458764, Immunoproteasome inhibitors for the treatment of Alzheimer’s disease (5R01AG073122-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10458764. Licensed CC0.

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