{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:18:59Z","timestamp":1787498339746,"version":"build-2736575974"},"reference-count":64,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Human African trypanosomiasis (HAT) is caused by the protozoan\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma brucei<\/jats:named-content>\n                    . New drugs are needed to treat HAT because of undesirable side effects and difficulties in the administration of the antiquated drugs that are currently used. In human proliferative diseases, protein tyrosine kinase (PTK) inhibitors (PTKIs) have been developed into drugs (e.g., lapatinib and erlotinib) by optimization of a 4-anilinoquinazoline scaffold. Two sets of facts raise a possibility that drugs targeted against human PTKs could be \u201chits\u201d for antitrypanosomal lead discoveries. First, trypanosome protein kinases bind some drugs, namely, lapatinib, CI-1033, and AEE788. Second, the pan-PTK inhibitor tyrphostin A47 blocks the endocytosis of transferrin and inhibits trypanosome replication. Following up on these concepts, we performed a focused screen of various PTKI drugs as possible antitrypanosomal hits. Lapatinib, CI-1033, erlotinib, axitinib, sunitinib, PKI-166, and AEE788 inhibited the replication of bloodstream\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>\n                    , with a 50% growth inhibitory concentration (GI\n                    <jats:sub>50<\/jats:sub>\n                    ) between 1.3 \u03bcM and 2.5 \u03bcM. Imatinib had no effect (i.e., GI\n                    <jats:sub>50<\/jats:sub>\n                    &gt; 10 \u03bcM). To discover leads among the drugs, a mouse model of HAT was used in a proof-of-concept study. Orally administered lapatinib reduced parasitemia, extended the survival of all treated mice, and cured the trypanosomal infection in 25% of the mice. CI-1033 and AEE788 reduced parasitemia and extended the survival of the infected mice. On the strength of these data and noting their oral bioavailabilities, we propose that the 4-anilinoquinazoline and pyrrolopyrimidine scaffolds of lapatinib, CI-1033, and AEE788 are worth optimizing against\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>\n                    in medicinal chemistry campaigns (i.e., scaffold repurposing) to discover new drugs against HAT.\n                  <\/jats:p>","DOI":"10.1128\/aac.01691-13","type":"journal-article","created":{"date-parts":[[2014,1,28]],"date-time":"2014-01-28T00:28:10Z","timestamp":1390868890000},"page":"2202-2210","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["New Chemical Scaffolds for Human African Trypanosomiasis Lead Discovery from a Screen of Tyrosine Kinase Inhibitor Drugs"],"prefix":"10.1128","volume":"58","author":[{"given":"Ranjan","family":"Behera","sequence":"first","affiliation":[{"name":"Department of Cellular Biology, University of Georgia, Athens, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology, University of Georgia, Athens, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kojo","family":"Mensa-Wilmot","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology, University of Georgia, Athens, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2005.08.026"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio837"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1006\/biol.1996.0028"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(98)01433-4"},{"key":"e_1_3_2_6_2","first-page":"91","article-title":"The cell cycle of parasitic protozoa: potential for chemotherapeutic exploitation","volume":"5","author":"Hammarton TC","year":"2003","unstructured":"HammartonTCMottramJCDoerigC. 2003. 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