Indirubin inhibitors of Leishmania mexicana CRK3 Cyclin Dependent Kinase
Poster Mar 07, 2007
Dawn Taylor, Karen M. Grant and Nicholas J. Westwooda
The indirubins are known inhibitors of cyclin dependent kinases (CDKs), including CRK3 from the protozoan parasite Leishmania mexicana, which is essential for proliferation of the disease Leishmaniasis. Subsequent investigations into the pharmacological properties of the indirubins show them to be competitive ATPbinding site inhibitors of the CDKs.
The structural basis for selectivity and potency has been clarified with the crystallisation of a number of the target protein kinases in complex with indirubin inhibitors. In our hands, indirubins substituted at both the 3' and 5-positions exhibit significant selectivity as inhibitors of CRK3 compared with CDK1/cyclin B in vitro.
Immobilisation of our indirubin scaffold onto Affi-Gel beads via a polyethylene glycol linker has been carried out for use in affinity matrix chromatography experiments designed to access and confirm both known and potentially new protein targets. The overall aim of this study is to identify an indirubin lead compound that is selective against CRK3 for future anti-Leishmanial drug development.