A second round of structure activity relationship (SAR) modelling of the most active and selective CK1d inhibitors has produced a marked improvement in activity and selectivity against the main anti-target.
Following successful in silico modelling and screening of CK1d a panel of over 600 candidate compounds were identified. To date, around half of these have been tested in an in vitro assay with a good percentage of those tested showing strong activity. After the first round of SAR two compounds PS110 and PS278 were shown to knock down levels of Tau phosphorylation in a recently published human neuronal cell line model over-expressing Tau protein, as measured using proprietary pTau 2.0 & 3.0 assays that are only available through PS Biomarker Services.
In the latest round of SAR analysis we have significantly improved the anti-Ck1d activity of both compounds and for PS278 also substantially improved its selectivity by over seven-fold against the main anti-target. Further profiling of the developed SAR compounds including in vitro and in vivo pharmacokinetic studies will be completed during the summer and evaluation of biological activity assessed in a whole organism model with results expected in the autumn.
"The extensive CK1D in vitro testing programme has been matched with innovative modelling software and has led to new areas of synthetic interest. Molecules from this programme are being tested and early data suggests greater potency and selectivity. Confirmation of these studies will allow selection of the molecules to enter the key in vivo studies in Q3/4 2012." Professor Bill Dawson, non-executive director of Proteome Sciences said, adding "I am delighted to see the successful interaction between the biological modelling and informatics programmes. It is key to explore the chemical space effectively and quickly so that these interesting series may be rapidly exploited."