Typically at Sygnature, a number of hit series, discovered during hit identification, are assessed in order to establish which should be optimised. Hit-to-lead projects typically run for 6 – 9 months and two to three lead series are usually selected for progression into lead optimisation.
A key objective of the hit-to-lead phase is to rapidly confirm that a true structure-activity relationship (SAR) exists within a number of hit series for the biological target. In addition, due consideration is made towards starting to improve physico-chemical properties, improving metabolic stability and establishing the way forward with improving potency and selectivity of compounds for the biological target of interest.
In silico profiling of compounds is also used by our medicinal chemists to focus synthetic strategies and scaffold core-hopping techniques can be used to generate new hit series with improved properties. Sygnature has a large number of novel core templates generated through our European Lead Factory participation which are available for unique enumeration in client programs.
The ultimate goal of a hit-to-lead programme is to identify the likely scope of key issues which will need to be addressed in the lead optimisation phase in order to help to select the more promising hit series for further optimisation.