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Cryptosporidiosis often causes chronic infection in immunocompromised people and gastrointestinal injury in malnourished children, leading to wasting, stunting, and cognitive impairment. Current treatment for cryptosporidiosis fails in these vulnerable populations, highlighting the need for new medicines. Here we describe the anti-<jats:italic>Cryptosporidium<\/jats:italic> efficacy, pharmacokinetics, and safety of a bumped kinase inhibitor BKI-1708. BKI-1708 inhibits the essential molecular target, calcium-dependent protein kinase 1 (CDPK1), which is highly expressed in the major proliferative stages of the parasite life cycle.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and Findings<\/jats:title>\n<jats:p>Efficacy was demonstrated in the <jats:italic>Cryptosporidium parvum<\/jats:italic> IFN\u03b3-KO mouse infection and calf diarrhea models. Dose response in the mouse model demonstrated oral doses as low as 15\u2009mg\/kg administered daily for 3 days completely suppressed oocyst shedding. Metabolite profiling in pre-clinical species and human hepatocytes identified an active metabolite, M2, which retains sub-micromolar activity against <jats:italic>C. parvum<\/jats:italic>. Pharmacokinetic analysis of BKI-1708 and M2 in mice demonstrates good systemic exposure, important for treating biliary and upper respiratory infections in some cases of cryptosporidiosis. In mice, M2 reaches 7-fold and &gt;3-fold higher levels over BKI-1708 in plasma and the gastrointestinal tract, respectively. Oral administration of M2 completely suppressed oocyst shedding in the mouse model at doses as low as 8\u2009mg\/kg for 3 days. Wide safety margins are demonstrated in mice, rats, and dogs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>BKI-1708 has characteristics of a safe and effective drug for treating <jats:italic>Cryptosporidium<\/jats:italic> infections in animal models and shows promise for use in humans. Moreover, BKI-1708 and M2 formed in vivo, offer an attractive prospect of a dually active preclinical candidate for the treatment of cryptosporidiosis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0013263","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:22:59Z","timestamp":1753896179000},"page":"e0013263","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Anti-Cryptosporidium efficacy of BKI-1708, an inhibitor of Cryptosporidium calcium-dependent protein kinase 1"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9374-5893","authenticated-orcid":true,"given":"Ryan","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Hulverson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah 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