# Zinc-targeting inhibitors of insulin-degrading enzyme

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $286,100

## Abstract

PROJECT SUMMARY/ABSTRACT
Insulin-degrading enzyme (IDE) is an evolutionarily and structurally distinctive zinc-metallopeptidase that is the
best characterized mediator of insulin catabolism in vivo. IDE is strongly implicated in the pathogenesis and
potential treatment of type 2 diabetes mellitus (T2DM) as well as other highly prevalent diseases. For more
than 60 years, pharmacological inhibition of IDE has been viewed as an attractive way to promote endogenous
insulin signaling and thereby treat T2DM, and the feasibility of this fundamental idea was recently confirmed in
vivo (Maianti et al., Nature 2014). Despite the considerable promise of IDE inhibitors as experimental probes
and as potential pharmacophores, only a limited number of inhibitors have emerged. Existing inhibitors do not
possess the properties needed to address a large number of outstanding questions about the fundamental
biology of IDE, such as the differing roles of intracellular and extracellular pools of IDE. Moreover, current IDE
inhibitors lack appropriate medicinal properties, such as oral bioavailability and long-term stability in vivo,
needed to be developed into drugs for clinical use.
The objective of this proposal is to use fragment-based drug design (FBDD) to develop a diverse set of potent,
selective, small-molecule, zinc-targeting IDE inhibitors suitable for use as experimental probes and/or as lead
compounds for future drug development. Specifically, in Aim 1, we will screen several custom libraries of
metal-binding pharmacophores (MBPs), synthesized in-house, to identify novel chemical moieties targeting the
catalytic zinc atom within the active site of IDE. In Aim 2, we will synthesize sublibraries of compounds
containing these zinc-targeting moieties; test them for potency, selectivity and other properties; then repeat this
process until IDE inhibitors with the desired set of features are obtained. In Aim 3, we will characterize key
properties of developed inhibitors, using a battery of in vitro, cell-based, and in vivo assays. An innovative goal
of this project is to develop compounds that are, to the greatest extent possible, selective for different
substrates of interest, a novel feature of IDE that results from its unusual tertiary structure and atypical
mechanism of substrate binding. Accordingly, throughout all phases of the project, we will test all compounds
against multiple substrates in parallel. Using this approach, we have so far identified >25 structurally diverse
MBPs that inhibit IDE with remarkable potency. Moreover, through the optimization of just a subset of
identified MBPs, we have already succeeded in developing drug-like compounds with nanomolar potency.
Notably, these novel compounds selectively inhibit the degradation of insulin and also show strong specificity
for IDE versus numerous other proteases. The successful completion of this project will result in novel IDE
inhibitors suitable for diverse experimental and medicinal applications...

## Key facts

- **NIH application ID:** 9993121
- **Project number:** 5R01GM115617-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** MALCOLM ARTHUR LEISSRING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $286,100
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993121

## Citation

> US National Institutes of Health, RePORTER application 9993121, Zinc-targeting inhibitors of insulin-degrading enzyme (5R01GM115617-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993121. Licensed CC0.

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