Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.
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The authors acknowledge the Wellcome Trust for funding (grants 092340, 105021, 100476, 101842, 079838 and 098051).
Nature thanks R. Guy, J. Mottram and the other anonymous reviewer(s) for their contribution to the peer review of this work.
These authors have shares in GlaxoSmithKline: P.G.W., S.D., T.J.M., K.D.R., S.C., R.L., S.G., M.Bo., H.P., P.C., G.D., D.G., S.G.-D. and J.M.F. The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Chart shows relative luminescence units (RLU) versus time from axenic amastigote rate-of-kill experiment with compound 7 (representative results for one of two independent experiments are shown; data are mean and s.d. of three technical replicates). Concentrations are as follows (µM): 50, open circles; 16.7, closed circles; 5.6, open squares; 1.85, closed squares; 0.62, open triangles; 0.21, closed triangles; 0.069, open inverted triangles; 0.023, closed inverted triangles, 0.0076, open diamonds and 0.0025, closed diamonds.
Extended Data Fig. 2 Linker-containing target molecules synthesized for chemical proteomic experiments and their corresponding EC50 values.
Potencies of the compounds in the cidal axenic and intra-macrophage assays are shown; data are from at least three independent replicates.
This file contains author contributions, methods, characterisation of compounds and ethical statements. It also contains supplementary figures S1-S74 and supplementary tables S1-S9.
This file contains Proteomic data from the work at Cellzome.
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Wyllie, S., Thomas, M., Patterson, S. et al. Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature 560, 192–197 (2018). https://doi.org/10.1038/s41586-018-0356-z
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