Hit to Lead

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.

We offer:

In Silico Profiling
Sygnature’s medicinal chemists have the software tools and skills to undertake an effective library design process. Typically properties such as logP, MW and PSA would be calculated for all enumerated compounds. This data would then be visualised and a compound selection made according to the design parameters for that project. Often, the aim would be to focus on a range of drug like properties relevant to gaining good oral bioavailability.
Parallel Chemistry Techniques
Sygnature has extensive experience of building diverse libraries based on novel scaffolds through our participation in the European Lead Factory screening libraries initiative. We can often make use of these efficient parallel chemistry techniques to prepare focused arrays for rapid in vitro screening and in vitro DMPK profiling to swiftly generate SAR on new hits. We design novel molecules that explore pharmacophoric features of selected hits and can then make use of parallel chemistry techniques to prepare focused arrays (typically up to of 50 compounds at 1 - 50mg scale) with chemical purities of >=95% (by LC-MS and NMR) for rapid in vitro screening and profiling.
Improving Metabolic Stability
Sygnature’s experienced medicinal chemists and DMPK scientists are often able to identify potential liabilities in hit molecules and propose alternative structures that may maintain key interactions whilst starting the process of improving physico-chemical properties and metabolic stability. Such exploratory designs will often establish a way forward to improve ADMET properties as well as potency and selectivity of compounds for the biological target of interest.
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