Aurora kinases have gained a great deal of attention as possible anticancer drug targets because these serine–threonine kinases are frequently overexpressed in human tumours.
For a research project on genetic instability and cellular proliferation caused by aurora kinase expression in several cancer entities, including multiple myeloma, the group of Dr Joe Lewis, Head of Chemical Biology Core Facility at the European Molecular Biology Laboratory (EMBL) Heidelberg, has been searching for novel aurora kinase inhibitors supplementing already known clinical aurora kinase inhibitors such as VX680.
The search for promising compounds was based on the screening of ProfilesTM from BICOLL’s library of plant metabolites.
Dr Lewis explained: ‘Bicoll’s idea of using pooled and fractionated small molecule collections, derived from endemic Asian plants, has already successfully led to the identification of hit compounds in various high-throughput screening processes in other cooperations. We were curious to find out whether natural products could also demonstrate their proof-of-concept for our biochemical screening methods.’
BICOLL provided a set of 1000 Profiles (equal to approximately 3000–10,000 different small molecules) to EMBL's biochemical screening program, which resulted in 18 hit clusters showing specific kinase activity. Because of the unexpectedly high hit rate of 2 per cent, the group of EMBL researchers elected to focus on four hit clusters for isolation and structure elucidation.
‘Within only three months and a second round of screening, BICOLL identified and structurally elucidated two pure compounds with interesting structural motifs for our client’s further development programs,’ commented Dr Kai Lamottke, Managing Director of BICOLL. ‘Subsequent investigation of our pure natural compound database, using the newly found structural motifs, additionally led to the testing in EMBL's protein–protein interaction test. Additional compounds for further structure–activity relationship could be identified.’