Three decades with kinases and marine invertebrates.

For over three decades, Laurent Meijer and his collaborators have investigated the regulation of the cell division cycle using marine invertebrate eggs and embryos as initial biological models. This fundamental research has lead to the identification and extensive characterization of a class of regulators, the cyclin-dependent kinases (CDKs), as well as other protein kinases regulators. This research has been driven by the fact that aberrant kinase activity is implicated in a variety of human diseases, including cancers.

Image: Starfish oocytes are large and transparent cells which can be isolated in huge amounts. Their properties greatly contributed to the success of the starfish oocyte model in investigations of the biochemical regulation of the cell cycle prophase/metaphase transition.

Using a small set of disease-relevant kinases as screening targets, several new families of pharmacological inhibitors have been identified, optimized and characterized from a highly diverse library of 45,000 compounds, rich in natural products. We have been particularly investigating marine natural products, as they are an original and relatively untapped source of novel drugs with great potential for pharmaceutical application.

A first pharmacological breakthrough: R-roscovitine

Among the initially identified compounds, Laurent Meijer identified R-roscovitine (2,6,9-trisubstituted purine). R-roscovitine (also named seliciclib) is currently in phase II trials in the USA against Lung and Nasopharyngeal Cancers, and in phase I against glomerulonephritis.

Image: R-roscovitine (seliciclib) is highly interesting selective CDK inhibitor that has been tested against cancers in over 250 patients in 13 countries.

Second generation inhibitors ready to take over

Following the discovery of R-roscovitine and other low molecular weight inhibitors, we have used and developed a variety of techniques to identify a new generation of improved drug candidates. Kinase/inhibitors co-crystal structure data, extensive structure/activity relationship studies carried out with purified enzymes, extensive selectivity investigations, detailed cellular effect studies, and animal experiments have allowed us to discover, characterize and patent several families of innovative kinase inhibitors with significant improvements over past inhibitors (including R-roscovitine).

The aim of ManRos Therapeutics is to bring these molecules into clinical development against severe human diseases, including cancers, Alzheimer’s disease, and some renal diseases.