Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Wyllie, S. et al. (2018) Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature, 560, pp. 192-197. (doi: 10.1038/s41586-018-0356-z) (PMID:30046105)

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.

• Item Type: Articles
• Additional Information: The authors acknowledge the Wellcome Trust for funding (grants 092340, 105021, 100476, 101842, 079838 and 098051).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Wyllie, S., Thomas, M., Patterson, S., Crouch, S., De Rycker, M., Lowe, R., Gresham, S., Urbaniak, M. D., Otto, T. D., Stojanovski, L., Simeons, F. R.C., Manthri, S., MacLean, L. M., Zuccotto, F., Homeyer, N., Pflaumer, H., Boesche, M., Sastry, L., Connolly, P., Albrecht, S., Berriman, M., Drewes, G., Gray, D. W., Ghidelli-Disse, S., Dixon, S., Fiandor, J. M., Wyatt, P. G., Ferguson, M. A.J., Fairlamb, A. H., Miles, T. J., Read, K. D., and Gilbert, I. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 25 July 2018
• Copyright Holders: Copyright © 2018 Springer Nature Ltd.
• First Published: First published in Nature 560:192-197
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher