Advancing Pantothenate Kinase Activation Therapy

Abstract Coenzyme A (CoA) is an essential cellular cofactor that carries carboxylic acid substrates in key metabolic pathways, including the citric acid cycle, sterol biosynthesis, amino acid metabolism, and fatty acid biosynthesis and oxidation. The pantothenate kinases (PANK) phosphorylates pantothenate (vitamin B5) in the first and rate-limiting step of the CoA biosynthetic pathway. Three genes encode four PANK isoforms in humans, PANK1α, 1β, 2, and 3, and the isoform expression levels in different tissues and sub-cellular compartments, together with potent feedback inhibition by CoA thioesters, control the intracellular CoA concentrations. Mutations in PANK2 are directly causative for Pantothenate Kinase-Associated Neurodegeneration (PKAN). PKAN, formerly called Hallervorden-Spatz syndrome, is an autosomal recessive movement disorder with onset in childhood and is characterized by neurodegeneration, progressive parkinsonism, and brain iron accumulation (NBIA). Our efforts began with the discovery of PZ-2891, an allosteric activator of PANK3 that counteracts the allosteric inhibition by acetyl CoA. PZ-2891 elevates CoA in cells, crosses the blood-brain barrier, and elevates CoA in the brains of mice. Most importantly, PZ-2891 rescues a conditional PKAN mouse model with CoA deficiency in neurons and corrects the growth defect, improves the movement disorder, and extends survival substantially. Through a major investment into this program, we were able to rapidly advance the development of PZ PANK activators, leading to the nomination of BBP-671 as a clinical candidate, which advanced into Phase I clinical trials. BBP-671 development has recently been stopped at this stage due to variable pharmacokinetics in humans. Here, using the BBP-671 roadmap, we propose to develop the next generation of PANK activators that overcome the pharmacokinetic limitations of BBP-671 using an iterative cycle of structure and metabolism- guided drug design. New modulators will be synthesized and evaluated in a staged testing cascade. Studies will also further explore the biochemical and cellular basis of PANK activation by PZ modulators, and we will test the hypothesis that activation by PZ modulators is associated with PANK isoform selectivity and overall affinity. Pharmacokinetic/Pharmacodynamic studies in mice will be used to study oral bioavailability, blood- brain penetration, and efficacy of new activators. The most efficacious compounds will then be tested in the SynCre+ PANK1 and PANK2 neuronal knockout mice for their ability to improve the PKAN phenotype. At this point, we aim to declare a new late-stage preclinical lead suitable for advancement.