Abstract
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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Change history
04 July 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41586-023-06364-2
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Acknowledgements
The authors acknowledge the Wellcome Trust for funding (grants 092340, 105021, 100476, 101842, 079838 and 098051).
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Nature thanks R. Guy, J. Mottram and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Contributions
In brief, S.W., M.D.U., T.D.O, H.P., M.Bo. and S.M. carried out the mode of action, genomic and proteomic studies. M.T., S.P. and S.A. carried out the chemistry studies. M.D.R., S.M., L.M.M. and L.Sa. carried out the parasite screening. S.C., L.S., F.R.C.S. and P.C. carried out the drug metabolism and pharmacokinetic studies. F.Z. and N.H. carried out the molecular modelling. R.L. and S.G. carried out the safety studies. S.W., M.T., S.P., M.D.R., R.L., S.G., M.D.U., L.M.M., F.Z., M.Be., G.D., D.W.G., S.G.-D., S.D., J.M.F., P.W.G., M.A.J.F., A.H.F., T.J.M., K.D.R. and I.H.G. designed experiments, managed parts of the project and contributed to the writing. See Supplementary Information for further details.
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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.
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Extended data figures and tables
Extended Data Fig. 1 Rate-of-kill of L. donovani axenic amastigotes by compound 7.
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.
Supplementary information
Supplementary Information
This file contains author contributions, methods, characterisation of compounds and ethical statements. It also contains supplementary figures S1-S74 and supplementary tables S1-S9.
Supplementary Data
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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DOI: https://doi.org/10.1038/s41586-018-0356-z
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