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Peer-reviewedCC BY 4.0The Journal of Biological Chemistry

A selective PanK3 activator increases coenzyme A levels in cellular and mouse models of pantothenate kinase-associated neurodegeneration

  • Jessica Regan1,2
  • Anasuya C. Pal1,2
  • Shalev Gihaz1
  • Richard E. Sutton1
  • Choukri Ben Mamoun1,3,4
4 affiliations
  1. 1Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
  2. 2Virtus Therapeutics Corporation, Groton, Connecticut, USA
  3. 3Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, Connecticut, USA
  4. 4Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
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Abstract

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare progressive neurodegenerative disorder associated with iron accumulation in the brain. The disease, which causes early immobility and often death by early adulthood, is caused by loss of function mutations in the human PANK2 gene, encoding a key enzyme in the biosynthesis of coenzyme A from pantothenic acid. To date, no disease-modifying therapy exists for PKAN, and current interventions are largely limited to symptomatic management. Herein, we report the identification of a new class of direct activators of human PANK3, termed VTACs, designed to compensate for the loss of PANK2 function. Using cellular and mouse models of PKAN, we demonstrate that a lead VTAC compound, VTAC-2, increases coenzyme A levels in PanK2-deficient cells and in the globus pallidus and substantia nigra, two brain regions prominently affected in PKAN patients. Moreover, the favorable physicochemical properties and oral bioavailability of VTAC-2 make this compound an attractive candidate for clinical evaluation for the treatment of PKAN.

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Cite

BibTeXRIS
BibTeX
@article{regan2026selective,
  title = {{A selective PanK3 activator increases coenzyme A levels in cellular and mouse models of pantothenate kinase-associated neurodegeneration}},
  author = {Jessica Regan and Anasuya C. Pal and Shalev Gihaz and Richard E. Sutton and Choukri Ben Mamoun},
  journal = {The Journal of Biological Chemistry},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jbc.2026.113567},
  url = {https://doi.org/10.1016/j.jbc.2026.113567},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A selective PanK3 activator increases coenzyme A levels in cellular and mouse models of pantothenate kinase-associated neurodegeneration
AU  - Jessica Regan
AU  - Anasuya C. Pal
AU  - Shalev Gihaz
AU  - Richard E. Sutton
AU  - Choukri Ben Mamoun
PY  - 2026
DA  - 2026/09/17
JO  - The Journal of Biological Chemistry
DO  - 10.1016/j.jbc.2026.113567
UR  - https://doi.org/10.1016/j.jbc.2026.113567
AB  - Pantothenate kinase-associated neurodegeneration (PKAN) is a rare progressive neurodegenerative disorder associated with iron accumulation in the brain. The disease, which causes early immobility and often death by early adulthood, is caused by loss of function mutations in the human PANK2 gene, encoding a key enzyme in the biosynthesis of coenzyme A from pantothenic acid. To date, no disease-modifying therapy exists for PKAN, and current interventions are largely limited to symptomatic management. Herein, we report the identification of a new class of direct activators of human PANK3, termed VTACs, designed to compensate for the loss of PANK2 function. Using cellular and mouse models of PKAN, we demonstrate that a lead VTAC compound, VTAC-2, increases coenzyme A levels in PanK2-deficient cells and in the globus pallidus and substantia nigra, two brain regions prominently affected in PKAN patients. Moreover, the favorable physicochemical properties and oral bioavailability of VTAC-2 make this compound an attractive candidate for clinical evaluation for the treatment of PKAN.
SN  - 0021-9258
SN  - 1083-351X
ER  -