A therapeutic approach to pantothenate kinase associated neurodegeneration

  • Nat Commun. 2018 Oct 23;9(1):4399. doi: 10.1038/s41467-018-06703-2.
Lalit Kumar Sharma  1  2  3 ,  Chitra Subramanian  1 ,  Mi-Kyung Yun  4 ,  Matthew W Frank  1 ,  Stephen W White  4 ,  Charles O Rock  1 ,  Richard E Lee  2 ,  Suzanne Jackowski  5
Affiliations
  • 1. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 2. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 3. Nurix, Inc, 1700 Owens Street, Suite 205, San Francisco, CA, 94158, USA.
  • 4. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 5. Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. [email protected].
PMID: 30352999 DOI: 10.1038/s41467-018-06703-2
Abstract

Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.

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