NEU-4438 is a lead for the development of drugs against Trypanosoma brucei, which causes human African trypanosomiasis. Optimized with phenotypic screening, targets of NEU-4438 are unknown. Herein, we present a cell perturbome workflow that compares NEU-4438's molecular modes of action to those of SCYX-7158 (acoziborole). Following a 6 h perturbation of trypanosomes, NEU-4438 and acoziborole reduced steady-state amounts of 68 and 92 unique proteins, respectively. After analysis of proteomes, hypotheses formulated for modes of action were tested: Acoziborole and NEU-4438 have different modes of action. Whereas NEU-4438 prevented DNA biosynthesis and basal body maturation, acoziborole destabilized CPSF3 and other proteins, inhibited polypeptide translation, and reduced endocytosis of haptoglobin-hemoglobin. These data point to CPSF3-independent modes of action for acoziborole. In case of polypharmacology, the cell-perturbome workflow elucidates modes of action because it is target-agnostic. Finally, the workflow can be used in any cell that is amenable to proteomic and molecular biology experiments.

2017-03-10·ACS Infectious Diseases2区 · 医学

From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis

2区 · 医学

Article

作者: Satoh, Takashi ; Tear, Westley ; Barros-Alvarez, Ximena ; Navarro, Miguel ; Pollastri, Michael P. ; Rojas, Domingo ; Devine, William G. ; Hol, Wim G. J. ; Ceballos-Perez, Gloria ; Buckner, Frederick S. ; Diaz-Gonzalez, Rosario ; Ranade, Ranae M.

Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.

PLoS Neglected Tropical Diseases2区 · 医学

Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign

2区 · 医学

ArticleOA

作者: Diaz, Rosario ; Rojas-Barros, Domingo I ; Navarro, Miguel ; Luengo-Arratta, Sandra A ; Martin, Jose Julio ; Gonzalez, Silvia ; Seixas, João D ; Berlanga, Manuela ; Colmenarejo, Gonzalo ; Fiandor, Jose Maria ; Manzano, Pilar ; Cordon-Obras, Carlos ; Crouch, Sabrinia ; Amata, Emanuele ; Jimenez, Elena ; Devine, William ; Ortega, Fatima ; Pollastri, Michael P

In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.

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适应症	最高研发状态	国家/地区	公司	日期
布氏锥虫感染	临床前	美国	Northeastern University	-
布氏锥虫感染	临床前	英国	St Andrews University Services Ltd.	-
布氏锥虫感染	临床前	西班牙	Instituto de Parasitología y Biomedicina López Neyra	-
布氏锥虫感染	临床前	英国	GSK Plc	-