PZ-2891

PZ-2891 is a modulator of pantothenate kinase (PanK).¹ It selectively inhibits PanK1β, PanK2, and PanK3 (IC₅₀s = 40.2, 0.7, and 1.3 nM, respectively) in the absence of acetyl-CoA over 468 other kinases and a panel of 72 receptors and ion channels at 10 µM. PZ-2891 (2.5 µM) reverses acetyl-CoA-induced inhibition of PanK3 in a cell-free assay, indicating activation of PanK3 activity. It increases intracellular CoA levels in wild-type PanK3-expressing HEK293T cells, but not in HEK293T cells expressing the catalytically inactive mutant PanK3^E138A. PZ-2891 increases survival in a mouse model of neuronal CoA deficiency induced by brain knockout of Pank1 and Pank2. It prevents infection of mosquitoes (A. stephensi) by P. falciparum.²

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1. Sharma, L.K., Subramanian, C., Yun, M.K., et al. A therapeutic approach to pantothenate kinase associated neurodegeneration. Nat. Commun. 9(1), (2018).

2. Simão-Gurge, R.M., Thakre, N., Strickland, J., et al. Activation of Anopheles stephensi pantothenate kinase and coenzyme A biosynthesis reduces infection with diverse Plasmodium species in the mosquito host. Biomolecules 11(6), 807 (2021).