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Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators
Rajendra Tangallapally1, Chitra Subramanian2, Mi-Kyung Yun3
1Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS1000, Memphis, Tennessee 38105, United States.
Abstract:
Conversion of pantothenate to phosphopantothenate in humans is the first dedicated step in the coenzyme A (CoA) biosynthesis pathway and is mediated by four isoforms of pantothenate kinase. These enzymes are allosterically regulated by acyl-CoA levels, which control the rate of CoA biosynthesis. Small molecule activators of the PANK enzymes that overcome feedback suppression increase CoA levels in cultured cells and animals and have shown great potential for the treatment of pantothenate kinase-associated neurodegeneration and propionic acidemias. In this study, we detail the further optimization of PANK pyridazine activators using structure-guided design and focus on the cellular CoA activation potential, metabolic stability, and solubility as the primary drivers of the structure-activity relationship. These studies led to the prioritization of three late-stage preclinical lead PANK modulators with improved pharmacokinetic profiles and the ability to substantially increase brain CoA levels. Compound 22 (BBP-671) eventually advanced into clinical testing for the treatment of PKAN and propionic acidemia.
Insights
Researchers optimized pantothenate kinase (PANK) activators to boost coenzyme A (CoA) levels. This led to new treatments for neurodegenerative diseases and metabolic disorders, with one compound entering clinical trials.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Pantothenate kinase (PANK) enzymes initiate coenzyme A (CoA) biosynthesis in humans.
- Acyl-CoA levels allosterically regulate PANK, controlling CoA production rates.
- PANK activators show therapeutic potential for pantothenate kinase-associated neurodegeneration (PKAN) and propionic acidemias.
Purpose of the Study:
- Optimize PANK pyridazine activators through structure-guided design.
- Enhance cellular CoA activation, metabolic stability, and solubility.
- Identify preclinical lead compounds with improved pharmacokinetics and brain CoA elevation.
Main Methods:
- Structure-guided design for PANK activator optimization.
- Evaluation of cellular CoA activation, metabolic stability, and solubility.
- Pharmacokinetic profiling and assessment of brain CoA levels.
Main Results:
- Prioritization of three late-stage preclinical PANK modulators.
- Demonstrated improvement in pharmacokinetic profiles.
- Substantial increase in brain CoA levels achieved with lead compounds.
Conclusions:
- Optimized PANK activators show promise for treating PKAN and propionic acidemia.
- Compound 22 (BBP-671) advanced to clinical testing.
- Structure-activity relationship studies successfully guided the development of effective PANK modulators.
