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

  • Nature. 2018 Aug;560(7717):192-197. doi: 10.1038/s41586-018-0356-z.
Susan Wyllie  1 ,  Michael Thomas  1 ,  Stephen Patterson  1 ,  Sabrinia Crouch  2 ,  Manu De Rycker  1 ,  Rhiannon Lowe  3 ,  Stephanie Gresham  3 ,  Michael D Urbaniak  1  4 ,  Thomas D Otto  5  6 ,  Laste Stojanovski  1 ,  Frederick R C Simeons  1 ,  Sujatha Manthri  1 ,  Lorna M MacLean  1 ,  Fabio Zuccotto  1 ,  Nadine Homeyer  1 ,  Hannah Pflaumer  7 ,  Markus Boesche  7 ,  Lalitha Sastry  1 ,  Paul Connolly  8 ,  Sebastian Albrecht  1 ,  Matt Berriman  5 ,  Gerard Drewes  7 ,  David W Gray  1 ,  Sonja Ghidelli-Disse  7 ,  Susan Dixon  9 ,  Jose M Fiandor  2 ,  Paul G Wyatt  1 ,  Michael A J Ferguson  1 ,  Alan H Fairlamb  1 ,  Timothy J Miles  10 ,  Kevin D Read  11 ,  Ian H Gilbert  12
Affiliations
  • 1. Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
  • 2. Global Health R&D, GlaxoSmithKline, Tres Cantos, Spain.
  • 3. David Jack Centre for R&D, GlaxoSmithKline, Ware, UK.
  • 4. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.
  • 5. Wellcome Sanger Institute, Cambridge, UK.
  • 6. Centre of Immunobiology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
  • 7. Cellzome GmbH, A GlaxoSmithKline Company, Heidelberg, Germany.
  • 8. GlaxoSmithKline, New Frontiers Science Park, Harlow, UK.
  • 9. Global Health R&D, GlaxoSmithKline, Stockley Park West, Uxbridge, UK.
  • 10. Global Health R&D, GlaxoSmithKline, Tres Cantos, Spain. [email protected].
  • 11. Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK. [email protected].
  • 12. Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK. [email protected].
PMID: 30046105 DOI: 10.1038/s41586-018-0356-z
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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