St. Jude Reference #SJ-18-0046
Coenzyme A (CoA) is an essential, cell autonomous cofactor derived from the vitamin pantothenate. CoA, acetyl-CoA and other thioesters required for mitochondrial energy production, lipid metabolism, epigenetic modification and the regulation of key steps in intermediary metabolism. Intracellular CoA/acetyl-CoA levels are controlled by pantothenate kinase (PanK). The St. Jude team has developed a new series of proprietary drug-like molecules with a wide spectrum of binding constants to PanK. Depending on their potency, these compounds act as either orthosteric inhibitors or allosteric activators of PanK in cells. These molecules are orally bioavailable, have favorable pharmacokinetic parameters, and are demonstrated to modulate tissue CoA levels in mice.
Compounds that activate PanK will enhance cellular CoA levels to support dysfunctional mitochondrial energy generation and intermediary metabolism deficiencies. Modulation of acetyl-CoA levels may be used to impact the epigenetic landscape and lipid metabolism. Because the reduction in liver CoA normalizes liver glucose production in the ob/ob mouse diabetes model, the high affinity inhibitors in the series may be useful in this disease context.
Coenzyme A, oxazoles, Pantothenate Kinase, Modulator, Mitochondria dysfunction, Alzheimer’s and Parkinson’s disease, diabetes, neurodegenerative diseases, microbial infections.
Granted patents or published applications
WO 2020/198526, published October 1, 2020; patent applications pending in the US, Canada, and EU
Related scientific references
Subramanian, C., Frank, M. W., Tangallapally, R., Yun, M. K., Edwards, A., White, S. W., Lee, R. E., Rock, C. O., and Jackowski, S. (2021) Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia. Sci. Transl. Med. 13, eabf5965
Sharma, L.K., Subramanian, C., Yun, M.K., Frank, M.W., White, S.W., Rock, C.O., Lee, R.E., and Jackowski, S. (2018). A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat. Commun. 9, 4399. (Some members of the oxazoles compound series have properties shared by the pantazine described above)
Leonardi, R., Rock, C.O., and Jackowski, S. (2014). Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance. Diabetologia 57, 1466-1475.
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