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The hit to lead phase is a critical phase of drug discovery programs, where the first set of compounds that demonstrated promising activity against the target are characterized. Hits identified through modern screening platforms such as a comprehensive high-throughput screening campaign, virtual screening, or screening by NMR, are characterized not only for their intrinsic potency but also for selectivity, general off-target activity, synthesis and patentability.

The goal of this stage is to select the most promising series, through limited structure-activity relationship (SAR) studies, to identify attractive compound classes to enter the Lead Optimization phase. The active compounds identified through the above screening platforms are clustered into families of compounds. Then, they are expanded by synthesizing a small number of analogues, to ensure that there are good structure-activity relationships against the target and against all the counter-screening assays. The most attractive series are then selected to enter the Lead Optimization phase.

Our Approach

Whether your therapeutic goal focuses on developing a small molecule, peptide or other biological drug, our team’s award-winning chemistry experience ensures your initial hits will see a significant improvement in their properties to fulfill the necessary criteria to enter the Lead Optimization phase. We do so through a combination of rigorous primary and secondary testing to assess potency, selectivity and off-target activity. Using physiochemical characterization, state-of-the-art facilities, pioneering scientific thinking and a collaborative approach, our team can make the difference, advancing your program while providing you with peace of mind.

Our Expertise

We can support hit-to-lead efforts in multiple therapeutic modalities, including small molecules, peptides, and biologics. Dedicated medicinal chemistry, peptide chemistry and biochemistry teams synthesize or prepare analogues, and fully qualify your original hit series, selecting the most promising compounds for the next phase. This includes the evaluation of chemical alternatives to hits with limited SAR, with low metabolic stability or poor selectivity, and patent space assessments to ensure the patentability of a novel chemical entity. A specifically designed validation funnel ensures each molecule is extensively tested to meet the criteria to enter the Lead optimization phase. Early ADME support provides additional information to ensure that the appropriate testing strategy will be in place when the compounds move to the next stage of the drug discovery process.

At IRBM, our capabilities include:

  • Hit ranking and clustering of hit series identified through screening platforms
  • In silico profiling of compounds, including scaffold hopping and pharmacophore modelling
  • Orthogonal testing to confirm the suitability of promising hit series
  • Computer-assisted drug design tools to test chemical modifications and evaluate scaffold-hopping approaches
  • Advanced chemical synthesis for hit expansion of small molecules and peptides
  • Multi-dimensional optimization of drug-like properties
  • Drug feasibility assessment based on patent space analysis, SAR and DMPK criteria
  • Initial improvement of ADME properties
  • NMR support for biophysical testing and structural characterization
  • Patent space evaluation to determine patentability of promising compounds and related freedom to operate

With a strategy designed specifically for your project, and a dedicated team working around the clock to ensure the generation of extremely promising compounds during the hit-to-lead phase, your drug discovery program advances smoothly and capably, delivering striking compounds and superior confidence in the overall success of your project.

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