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

• Published in: Nature (London) Vol. 560; no. 7717; pp. 192 - 197
• Main Authors: Wyllie, Susan, Thomas, Michael, Patterson, Stephen, Crouch, Sabrinia, De Rycker, Manu, Lowe, Rhiannon, Gresham, Stephanie, Urbaniak, Michael D., Otto, Thomas D., Stojanovski, Laste, Simeons, Frederick R. C., Manthri, Sujatha, MacLean, Lorna M., Zuccotto, Fabio, Homeyer, Nadine, Pflaumer, Hannah, Boesche, Markus, Sastry, Lalitha, Connolly, Paul, Albrecht, Sebastian, Berriman, Matt, Drewes, Gerard, Gray, David W., Ghidelli-Disse, Sonja, Dixon, Susan, Fiandor, Jose M., Wyatt, Paul G., Ferguson, Michael A. J., Fairlamb, Alan H., Miles, Timothy J., Read, Kevin D., Gilbert, Ian H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 13/106; 631/154/309; 631/92/609; 692/699/255/1715; Animals; Cell cycle; Confidence intervals; Cyclin-dependent kinase; Cyclin-Dependent Kinase 9 - chemistry; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - chemistry; Cyclin-Dependent Kinases - metabolism; Disease Models, Animal; Drug therapy; Genomes; Health aspects; Humanities and Social Sciences; Humans; Identification; Infections; Kinases; Leishmania donovani - drug effects; Leishmania donovani - enzymology; Leishmaniasis; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - parasitology; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Morbidity; Mortality; multidisciplinary; Organic chemistry; Parasites; Parasitic diseases; Pharmacokinetics; Pharmacology; Phosphotransferases; Proteins; Proteome - drug effects; Proteomics; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Reproducibility of Results; Science; Substrate Specificity; Vector-borne diseases; Visceral leishmaniasis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0356-z

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. A series of compounds are discovered for the treatment of visceral leishmaniasis, and cdc2-related kinase 12 (CRK12) is identified as the probable primary drug target.