title: Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis.
abstract: Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.
authors.affiliation: Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Patel
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Karver
authors.forename: Ranjan
authors.initials: R
authors.lastname: Behera
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Guyett
authors.forename: Catherine
authors.initials: C
authors.lastname: Sullenberger
authors.forename: Peter
authors.initials: P
authors.lastname: Edwards
authors.forename: Norma E
authors.initials: NE
authors.lastname: Roncal
authors.forename: Kojo
authors.initials: K
authors.lastname: Mensa-Wilmot
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D007202:Indicators and Reagents; D000077341:Lapatinib; D009025:Morpholines / Q000494:pharmacology; D058069:Neglected Diseases; D010770:Phosphotransferases / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D004396:Coloring Agents; D007202:Indicators and Reagents; D009025:Morpholines; D011799:Quinazolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D014344:Trypanocidal Agents; D000077341:Lapatinib; C420268:Canertinib; D010770:Phosphotransferases; D066246:ErbB Receptors; C022616:thiazolyl blue