PZ-2891

Description: PZ-2891 is a novel, potent, orally bioavailable, and brain penetrant allosteric activator of Pantothenate kinase (PANK). It acts as both an orthosteric inhibitor with IC50 of 1.3 nM and an allosteric activator of PANK3 in the presence of acetyl-CoA in biochemical assays. 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). 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.

References: Nat Commun. 2018 Oct 23; 9(1):4399.