Cyclin-dependent kinase 12, a novel drug target for visceral leishmaniasis

Wyllie, Susan and Thomas, Michael and Patterson, Stephen and Crouch, Sabrinia and De Rycker, Manu and Lowe, Rhiannon and Gresham, Stephanie and Urbaniak, Michael Daniel and Otto, Thomas D. and Stojanovski, Laste and Simeons, Frederick R. C. and Manthri, Sujatha and MacLean, Lorna M. and Zuccotto, Fabio and Homeyer, Nadine and Pflaumer, Hannah and Boesche, Markus and Sastry, Lalitha and Connolly, Paul and Albrecht, Sebastian and Berriman, Matt and Drewes, Gerard and Gray, David W. and Ghidelli-Disse, Sonja and Dixon, Susan and Fiandor, Jose M. and Wyatt, Paul G. and Ferguson, Michael A. J. and Fairlamb, Alan H. and Miles, Timothy J. and Read, Kevin D. and Gilbert, Ian H. (2018) Cyclin-dependent kinase 12, a novel drug target for visceral leishmaniasis. Nature, 560. pp. 192-197. ISSN 0028-0836

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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:
Journal Article
Journal or Publication Title:
Nature
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1000
Subjects:
ID Code:
126588
Deposited By:
Deposited On:
26 Jul 2018 08:22
Refereed?:
Yes
Published?:
Published
Last Modified:
24 Sep 2020 04:01