Full length articleExtended-spectrum antiprotozoal bumped kinase inhibitors: A review

- Many apicomplexan calcium-dependent protein kinases (CDPKs) are validated drug targets.
- These CDPKs have atypically small gatekeeper residues and are inhibited by bumped kinase inhibitors (BKIs).
- Highly selective ATP-competitive BKIs inhibit apicomplexan parasites growth at concentrations non-toxic to mammalian cells.
- A proof-of-concept therapeutic potential have been demonstrated in animal model of infections for some BKIs.
- BKIs have potential as therapeutics for diseases caused by apicomplexan pathogens.

Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors.

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