Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium.

The protozoan protein kinase calcium-dependent protein kinase 1 (CDPK1) has emerged as a potential therapeutic target for the treatment of cryptosporidiosis. A focused screen of known kinase inhibitors identified a pyridopyrimidinone as a new chemotype of Cryptosporidium parvum (Cp) CDPK1 inhibitors. Structural comparison of CpCDPK1 to two representative human kinases, RIPK2 and Src, revealed differences in the positioning of the αC-helix that was used in the design of a potent pyridopyrimidinone-based CpCDPK1 inhibitor 7 (a.k.a. UH15-16, IC ₅₀ = 10 nM), which blocked the growth of three C. parvum strains (EC ₅₀ = 12-40 nM) as well as C. hominis (EC ₅₀ = 85 nM) in HCT-8 host cells. Pharmacokinetic and tissue distribution analyses indicated that 7 had low systemic exposure after oral administration, but high gastrointestinal concentration, as well as good Caco-2 cell permeability. Finally, 7 demonstrated partial efficacy in an IL-12 knock-out mouse model of acute cryptosporidiosis.
Competing Interests: Declaration of Competing Interest WCVV is an owner/officer of ParaTheraTech Inc, a company which is seeking to bring bumped kinase (e.g. CDPK1) inhibitors to the animal health market. All other authors declare no interests.
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