The key objective of the hit-to-lead phase is to rapidly assess a number of hit clusters in order to identify 2 or 3 hit series that have the best potential to develop into drug-like leads.
This process starts by confirming that a true structure-activity relationship (SAR) exists within a number of hit series for the biological target. In addition, an early assessment is made of in-vitro ADMET properties to help select the most promising leads for optimisation. Hit-to-lead projects typically run for 6 – 9 months.
Sygnature has well-established infrastructure and expertise to conduct effective hit-to-lead projects in a timely manner:
- Our high throughput chemistry laboratory has been operational for 5 years producing diverse 3-dimensional, drug-like libraries for the European Lead Factory allowing client projects rapid access to hit expansion libraries.
- In-silico profiling of compounds can help to focus synthetic strategies and enable scaffold core-hopping techniques which can be used to generate new hit series with improved properties
- Sygnature’s experienced teams are often able to identify potential liabilities in hit molecules through an appropriate screening cascade and propose alternative structures that may maintain key interactions whilst starting the process of improving physico-chemical properties and metabolic stability.
- A wide range of in-vitro ADME and in-vitro Toxicity assays are available at Sygnature to allow hit profiling.
Rigorous early assessment of the available hits has a major impact on the time required for optimisation. Sygnature has a track record of delivering lead series that can be quickly optimised to robust candidate drugs.