# Pilot studies to characterize CDKL5 inhibitors

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2020 · $443,988

## Abstract

Pathological mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD,
OMIM 300203, 300672), a relatively common genetic cause of early-life epilepsy. Recent analysis of genetic
variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. In other words, loss
of kinase function seems equivalent to loss of the protein.
 Big gaps are present in rodent models of CDD. A key feature is missing in these models: severe epilepsy.
Specific inhibitors of CDKL5 are essential for addressing the role of CDKL5 without confounding chronic effects
of genetic CDKL5 deletion. A key waypoint in the path to address this question is knowledge of specific CDKL5
substrates. Our collaborator, Dr. Sila Ultanir, has determined that microtubule end-binding protein 2 (EB2) is a
specific CDKL5 substrate and has developed a phoshospecific antibody. With this tool in hand, our immediate
goal in this pilot project is to use this read-out of CDKL5 activity to identify sensitive and specific CDKL5 inhibitors
in brain tissues. Our collaborators, Dr. Axtman and Ms. Wells, have identified additional compounds. We will use
these inhibitors to address our hypothesis that the acute blockade of CDKL5 activity has unique effects on
hippocampal signaling and function compared to chronic knock-out through 2 aims: 1) Identify sensitive and
specific inhibitors of CDKL5 and 2) Determine effect of acute inhibition of CDKL5 on hippocampal synaptic
function and plasticity. Two developmental time points will be studied.
 Overall Impact: Our goal in this pilot project is to identify a CDKL5 inhibitor. This will allow us to bypass the
gaps in rodent models of human CDD. In future studies, we hypothesize that specific CDKL5 kinase inhibitors
will be necessary to fully probe and understand CDKL5 neuronal function throughout development. Since CDD
is a strong candidate for gene therapy, an important clinical question is whether gene replacement of CDKL5
later in life improves symptoms. Our future experiments are necessary to determine whether such therapy may
have an optimal developmental therapeutic window. Further, it may reveal that some symptoms of CDD do not
depend on CDKL5 function later in life, as these were triggered developmentally, and will require alternative
interventions beyond gene replacement.

## Key facts

- **NIH application ID:** 9986104
- **Project number:** 1R21NS112770-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** TIMOTHY A BENKE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,988
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986104

## Citation

> US National Institutes of Health, RePORTER application 9986104, Pilot studies to characterize CDKL5 inhibitors (1R21NS112770-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9986104. Licensed CC0.

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