The aims of Professor Linardopoulos' team are to identify and validate new molecular targets and to develop drugs through the process of hit generation, lead identification/optimisation and candidate selection.
Furthermore, they aim to identify tumour types and patient subgroups that would benefit from specific treatments. To achieve these aims, their programme encompasses both basic research and drug discovery components.
The research of the Drug Target Discovery Team has focused on mitosis, in particular, the Aurora and MPS1 kinases. Aurora kinases have been found to be overexpressed in a broad range of human tumours, including primary colorectal carcinoma, breast, ovarian, gliomas and pancreatic cancers. MPS1 is a mitotic checkpoint kinase and its activity is enhanced upon activation of the spindle checkpoint with anti-mitotic drugs.
The misregulation of these kinases and the association with genetic instability and aneuploidy in tumours has made these genes attractive targets for anticancer drug discovery.
The team is also focusing on centrosome amplification and aneuploidy. Precise control of centrosome number is crucial for bipolar spindle assembly and accurate transmission of genetic material to daughter cells. Failure to properly control centrosome number results in supernumerary centrosomes, which are frequently found in a wide variety of human cancers.
One mechanism frequently utilised by cancer cells to escape death caused by multipolar mitoses is the clustering of supernumerary centrosomes into bipolar spindles. The team has successfully screened RNAi and small molecule inhibitor libraries to identify genes involved in the clustering of extra centrosomes.
They have identified a number of candidate genes as novel targets for inhibition of centrosome clustering and have initiated a programme to develop small molecule inhibitors designed to target cancer cells with centrosome amplification.