- PKAN results from loss-of-function PANK2 mutations causing impaired CoA biosynthesis, progressive neurodegeneration, and brain iron accumulation; no disease-modifying therapies currently exist.
- A novel class of selective human PANK3 activators, VTACs, was identified to compensate for PANK2 deficiency by directly stimulating PANK3 activity.
- Lead compound VTAC-2 restores cellular and mouse brain CoA to wild-type levels and shows favourable physicochemical properties and oral bioavailability for clinical evaluation.
J Biol Chem. 2026 Sep 17:113567. doi: 10.1016/j.jbc.2026.113567. Online ahead of print.
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 cell and animal models of PanK2 deficiency, we demonstrate that a lead VTAC compound, VTAC-2, restores CoA levels to wild-type levels both in cells and in mouse brain. 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.
PMID:42754166 | DOI:10.1016/j.jbc.2026.113567
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