Protein kinase inhibitors from the New Caledonian rainforest

Protein kinases constitute an important group of enzymes that play a key role in the essentially all physiological processes. Abnormal phosphorylation is a common feature of many human diseases. Among the 518 different protein kinases identified in humans much attention has been focused on cyclin-dependant kinases such CDK1, 2, 3, 4, 5, 6, 7, 9. CDKs trigger and coordinate the cell division cycle, key neuronal functions, and cell death. Numerous CDKs deregulations have been described in tumors and neurodegenerative diseases. Consequently, these enzymes constitute some interesting molecular targets in the search for selective inhibitors against cell proliferation and cell death. The search for CDKs inhibitors requires several steps: (1) to set up a rapid bioassay using the purified kinase as target, (2) to realize a biological screening of molecules or crude extracts collections. (3) to evaluate the selectivity of pure compounds on a series of selected kinases, and (4) to establish the mechanism of action of the selected inhibitor by using different methods (co-cristallisation). A biological screen on CDK1/cyclin B has been realized on 2480 EtOAc crude extracts prepared from 1200 New-Caledonian plant. Using a strategy, which combines a standardized HPLC fractionation with the robotized biological assay, we have characterized three series of compounds including phenanthrenes from Appendicula reflexa Blume (Orchidaceae), aristolactams from Goniothalamus dumontetii R.M.K. Saunders & Munzinger (Annonaceae) and flavones from Lethedon microphylla (Guillaumin) Kosterm (Thymelaeaceae). This study, which allowed the discovery of a new species belonging to a genus described for the first time in New-Caledonia [1], highlights the absolute necessity to preserve the biodiversity. Reference: 1. Saunders, R.M.K., Munzinger, J. (2007) Bot. J. Linn. Soc. 155: 497–503.