Hit-to-Lead Or Lead Identification

The Hit-to-lead phase is to filter several hit compounds that would condense into 2 or 3 Hit series that have the best potential to lead candidates. Once a hit series is confirmed to demonstrate acceptable SAR understanding, engagement of the hit molecule with the biological target can be confirmed. Hit series with true target engagement are then advanced down the screening cascade in the program. In addition, evaluation of in-vitro ADMET properties is important to determine suitable leads per the predefined criteria. Hit-to-lead projects typically run for 6 – 9 months. Rigorous early assessment of the available hits has a major impact on the time required for lead identification.

Aragen IDD has a track record of delivering lead series that can be quickly optimised to robust candidate drugs. IDD teams typically work on setting the cut-offs on the following parameters for the successful candidate to be declared a lead :

• Cell-based assay in addition to the primary biochemical and selectivity assay data
• In-vitro safety (cytotoxicity assay) if relevant on appropriate cell lines
• Clear indicators as proof mechanism of action (MoA)
• Advanced ADME profiling such as 
  • Cyp inhibition data
  • Metabolic stability and identification in relevant species
  • Efflux ratio determination in a suitable permeability assay
  • Rodent PK optimization

Aragen IDD has the requisite infrastructure and resources to conduct efficient and effective hit-to-lead studies and advance a good lead to be optimized further.