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. Epub 2018 Jul 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase 9 / chemistry
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / chemistry
  • Cyclin-Dependent Kinases / metabolism
  • Disease Models, Animal
  • Humans
  • Leishmania donovani / drug effects*
  • Leishmania donovani / enzymology*
  • Leishmaniasis, Visceral / drug therapy*
  • Leishmaniasis, Visceral / parasitology*
  • Mice
  • Molecular Docking Simulation
  • Molecular Targeted Therapy*
  • Proteome / drug effects
  • Proteomics
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Reproducibility of Results
  • Substrate Specificity

Substances

  • Proteome
  • Pyrazoles
  • Pyrimidines
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
  • Cyclin-Dependent Kinases