{"id":{"repo_id":"houston","oai_identifier":"oai:uh-ir.tdl.org:10657/18327"},"canonical_url":"https://search.dev.ndltd.org/etd/houston/oai:uh-ir.tdl.org:10657/18327","repository":{"repo_id":"houston","name":"University of Houston","base_url":"https://uh-ir.tdl.org/server/oai/request"},"display":{"title":"Novel Design Strategy for Potent and Selective CDPK1 Inhibitors for Cryptosporidiosis","abstract":"Calcium – dependent protein kinase 1 (CDPK1) is a key enzyme functioning in cell motility of Cryptosporidium parvum (Cp) and C. hominis, the parasitic protozoa accountable for life-threatening diarrhea in young children and immunocompromised individuals worldwide. The unmet clinical need for the treatment of cryptosporidiosis due to the shortage of effective therapeutics has provoked the pursuit of several anti-cryptosporidium approaches. Among those, small molecules targeting the ATP-binding site of CDPK1 have held promise; however, none of the original series of CDPK1 inhibitors has successfully been used in humans due to various toxicities. Recently, UH15-16 that contains a pyridopyrimidinone scaffold, was reported as a novel class of CDPK1 inhibitors showing good Cp growth inhibition (IC50 = 0.04 μM) in HCT-8 host cells and no acute toxicity in mice. However, UH15-16 also moderately inhibited human Src kinase (IC50 = 0.28 μM), which raises a toxicity concern. Thus, enhancement of kinase selectivity was needed. Herein, we demonstrated that targeting a back pocket created by a distinct feature of the CDPK1 αC-helix efficiently enables enhancement of selectivity over human kinases. The structure-activity relationship (SAR) study of pyridopyrimidinone analogs also provided insights into CDPK1 inhibitor optimization. These efforts produced WIN1-158 as a 2nd - generation pyridopyrimidinone based CDPK1 inhibitor that provided greater selectivity (> 1,000-fold) against human Src kinase as well as other human kinases while retaining Cp growth inhibition (IC50 <10 nM) in HCT-8 host cells. This study will pave a new way to develop potent and selective CDPK1 inhibitors to fight against cryptosporidiosis.","abstract_html":"Calcium – dependent protein kinase 1 (CDPK1) is a key enzyme functioning in cell motility of Cryptosporidium parvum (Cp) and C. hominis, the parasitic protozoa accountable for life-threatening diarrhea in young children and immunocompromised individuals worldwide. The unmet clinical need for the treatment of cryptosporidiosis due to the shortage of effective therapeutics has provoked the pursuit of several anti-cryptosporidium approaches. Among those, small molecules targeting the ATP-binding site of CDPK1 have held promise; however, none of the original series of CDPK1 inhibitors has successfully been used in humans due to various toxicities. Recently, UH15-16 that contains a pyridopyrimidinone scaffold, was reported as a novel class of CDPK1 inhibitors showing good Cp growth inhibition (IC50 = 0.04 μM) in HCT-8 host cells and no acute toxicity in mice. However, UH15-16 also moderately inhibited human Src kinase (IC50 = 0.28 μM), which raises a toxicity concern. Thus, enhancement of kinase selectivity was needed. Herein, we demonstrated that targeting a back pocket created by a distinct feature of the CDPK1 αC-helix efficiently enables enhancement of selectivity over human kinases. The structure-activity relationship (SAR) study of pyridopyrimidinone analogs also provided insights into CDPK1 inhibitor optimization. These efforts produced WIN1-158 as a 2nd - generation pyridopyrimidinone based CDPK1 inhibitor that provided greater selectivity (> 1,000-fold) against human Src kinase as well as other human kinases while retaining Cp growth inhibition (IC50 <10 nM) in HCT-8 host cells. This study will pave a new way to develop potent and selective CDPK1 inhibitors to fight against cryptosporidiosis.","abstract_has_math":false,"creators":["Wijitrmektong, Wissarut 1988-"],"institution":"University of Houston","degree_name":"Doctor of Philosophy","degree_level":null,"degree_discipline":"Pharmacology","degree_department":null,"school":null,"contributors":[],"advisors":["Cuny, Gregory D."],"committee_chairs":[],"committee_members":["Udugamasooriya, Gomika","Antunes, Dinler Amaral","Gilbertson, Scott R.","Das, Joydip"],"year":2024,"date_issued":"2024-12","date_published":"2024-12","updated_at":"2026-07-24T02:32:47Z","subjects":["Medicinal chemistry","Pharmaceutical chemistry","Organic chemistry"],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10657/18327","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Cuny, Gregory D."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Udugamasooriya, Gomika","Antunes, Dinler Amaral","Gilbertson, Scott R.","Das, Joydip"]},{"key":"dc:creator","label":"Author","values":["Wijitrmektong, Wissarut 1988-"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-01-22T09:18:18Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-12"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmacology"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Houston"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Medicinal chemistry","Pharmaceutical chemistry","Organic chemistry"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10657/18327"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Calcium – dependent protein kinase 1 (CDPK1) is a key enzyme functioning in cell motility of Cryptosporidium parvum (Cp) and C. hominis, the parasitic protozoa accountable for life-threatening diarrhea in young children and immunocompromised individuals worldwide. The unmet clinical need for the treatment of cryptosporidiosis due to the shortage of effective therapeutics has provoked the pursuit of several anti-cryptosporidium approaches. Among those, small molecules targeting the ATP-binding site of CDPK1 have held promise; however, none of the original series of CDPK1 inhibitors has successfully been used in humans due to various toxicities. Recently, UH15-16 that contains a pyridopyrimidinone scaffold, was reported as a novel class of CDPK1 inhibitors showing good Cp growth inhibition (IC50 = 0.04 μM) in HCT-8 host cells and no acute toxicity in mice. However, UH15-16 also moderately inhibited human Src kinase (IC50 = 0.28 μM), which raises a toxicity concern. Thus, enhancement of kinase selectivity was needed. Herein, we demonstrated that targeting a back pocket created by a distinct feature of the CDPK1 αC-helix efficiently enables enhancement of selectivity over human kinases. The structure-activity relationship (SAR) study of pyridopyrimidinone analogs also provided insights into CDPK1 inhibitor optimization. These efforts produced WIN1-158 as a 2nd - generation pyridopyrimidinone based CDPK1 inhibitor that provided greater selectivity (> 1,000-fold) against human Src kinase as well as other human kinases while retaining Cp growth inhibition (IC50 <10 nM) in HCT-8 host cells. This study will pave a new way to develop potent and selective CDPK1 inhibitors to fight against cryptosporidiosis."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Novel Design Strategy for Potent and Selective CDPK1 Inhibitors for Cryptosporidiosis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Cuny, Gregory D."],"dc:contributor.committeemember":["Udugamasooriya, Gomika","Antunes, Dinler Amaral","Gilbertson, Scott R.","Das, Joydip"],"dc:creator":["Wijitrmektong, Wissarut 1988-"],"dc:date.accessioned":["2025-01-22T09:18:18Z"],"dc:date.issued":["2024-12"],"dc:description.abstract":["Calcium – dependent protein kinase 1 (CDPK1) is a key enzyme functioning in cell motility of Cryptosporidium parvum (Cp) and C. hominis, the parasitic protozoa accountable for life-threatening diarrhea in young children and immunocompromised individuals worldwide. The unmet clinical need for the treatment of cryptosporidiosis due to the shortage of effective therapeutics has provoked the pursuit of several anti-cryptosporidium approaches. Among those, small molecules targeting the ATP-binding site of CDPK1 have held promise; however, none of the original series of CDPK1 inhibitors has successfully been used in humans due to various toxicities. Recently, UH15-16 that contains a pyridopyrimidinone scaffold, was reported as a novel class of CDPK1 inhibitors showing good Cp growth inhibition (IC50 = 0.04 μM) in HCT-8 host cells and no acute toxicity in mice. However, UH15-16 also moderately inhibited human Src kinase (IC50 = 0.28 μM), which raises a toxicity concern. Thus, enhancement of kinase selectivity was needed. Herein, we demonstrated that targeting a back pocket created by a distinct feature of the CDPK1 αC-helix efficiently enables enhancement of selectivity over human kinases. The structure-activity relationship (SAR) study of pyridopyrimidinone analogs also provided insights into CDPK1 inhibitor optimization. These efforts produced WIN1-158 as a 2nd - generation pyridopyrimidinone based CDPK1 inhibitor that provided greater selectivity (> 1,000-fold) against human Src kinase as well as other human kinases while retaining Cp growth inhibition (IC50 <10 nM) in HCT-8 host cells. 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