# PANK Activators for the treatment of pantothenate kinase-associated neurodegeneration

> **NIH NIH R43** · VIRTUS THERAPEUTICS CORPORATION · 2024 · $99,000

## Abstract

SUMMARY
Pantothenate kinase-associated neurodegeneration, PKAN, is a rare progressive
neurodegenerative disorder associated with iron accumulation in the brain. The disease causes
early immobility and often death by early adulthood. PKAN is caused by mutations in one of four
human pantothenate kinase genes, PANK2 gene, which encodes a mitochondrial pantothenate
kinase. Consistent with the clinical presentation of PKAN in humans, cell biological analyses from
patient-derived cells as well as phenotypic characterization of mouse models of PKAN have
demonstrated that the loss of PANK2 activity results in major metabolic, cellular and physiological
defects. To date, no specific or established therapy exists for PKAN with most treatments directed
towards managing symptoms and to slow disease progression. We hypothesize that activation of
the human PANK3 (hPANK3) enzyme would result in stimulation of CoA production in PANK2
mutated cells and would represent an ideal treatment of PKAN. Chemical screening and
subsequent medicinal chemistry optimization (SAR) of the lead chemotype identified 9 human
PANK3 activators (VTAC1-9) that strongly activate hPANK3 with AC50 values in the nM range.
These compounds do not affect the activity of human PANK1 or PANK2, show no toxicity against
four human cell lines and one primary human cell, and have desirable functionality and solubility
properties. Pharmacokinetics studies in mice with the early leads VTAC1 and VTAC2
demonstrated both plasma and brain exposure, excellent t½, and no apparent toxicity. Together
these data indicate that these compounds are ideal candidates for the development of an effective
and safe PKAN therapy. The goal of the parent grant and proposed research is to conduct
detailed characterization of active VTACs and a library of their analogs to identify late leads
that could be advanced towards future clinical development. Towards this end, we will
pursue the following three specific aims. In Aim 1, we will complete current SAR on this family
compounds by characterizing the biochemical activity, selectivity and physico-chemical properties
of an already synthesized 29 analogs and an additional 200 compounds to be evaluated on an
iterative basis. In Aim 2, we will conduct cell-based assays to identify compounds with excellent
in vitro therapeutic index and can restore biological activity in pank2-deficient cells. In Aim 3, we
will conduct ADME and PK analyses and evaluate the in vivo efficacy of VTAC1 and VTAC2 and
new leads from Aim 1 in pank2-/- mice and SynCrepank1fl/flpank2fl/fl mice by monitoring important
PKAN biological metrics including activation of the CoA metabolic pathway, iron homeostasis,
mitochondrial metabolism, and rescue of PKAN-like phenotypes. The success of these studies
will set the stage for future clinical evaluation of a lead activator of hPANK3 as a possible effective
and safe treatment for PKAN.

## Key facts

- **NIH application ID:** 11146095
- **Project number:** 3R43NS127740-02S1
- **Recipient organization:** VIRTUS THERAPEUTICS CORPORATION
- **Principal Investigator:** Jessica Regan
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,000
- **Award type:** 3
- **Project period:** 2023-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11146095

## Citation

> US National Institutes of Health, RePORTER application 11146095, PANK Activators for the treatment of pantothenate kinase-associated neurodegeneration (3R43NS127740-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11146095. Licensed CC0.

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