Using high-throughput screening, scientists can employ thousands of small-molecule chemical compounds to test or “probe” the effects of increasing or decreasing the activity of a biological target. This approach works in cell and animal models, making it one of the most powerful tools for target validation (the process of demonstrating that engaging a target provides meaningful therapeutic benefit).
Generating these chemical probes requires specialized expertise and facilities, and NCATS has built leading-edge collaborative services to meet those needs. NCATS’ chemical probe development experts collaborate with more than 200 investigators in the government, biopharmaceutical, academic and nonprofit sectors. These partnerships lead to probes used to study a diverse cross-section of human biology, focusing specifically on novel targets and untreatable diseases.
Probes enable researchers to investigate protein and cell functions and biological processes, and if appropriate, they can be optimized to become potential drug candidates. This process, called lead optimization, involves refining the chemical structure of a candidate molecule to improve its safety and effectiveness in treating a disease.
NCATS’ probe development activities also focus on finding more efficient ways to make probes, using probes to understand diseases and validating targets to treat diseases.
The NCATS Approach
The Center’s current focus is on developing chemical probes for “non-druggable” targets and pathways. NCATS scientists also work to develop new paradigms for high-throughput screening, informatics and chemistry to make probe development more efficient.
Compounds chosen for lead optimization undergo potency, selectivity, solubility and ADME (absorption, distribution, metabolism, and excretion)/pharmacokinetic optimization through the Center’s synthetic chemistry operation. This process narrows candidates to a smaller set of leads that are sufficiently advanced to begin formal preclinical development for a disease of interest.
- Fully automated, large-scale small molecule screening
- Experience with biochemical as well as cell- and organism-based assay technologies
- Target-based and phenotypic screening strategies
- Medicinal chemistry
- High-throughput parallel synthetic and analytical chemistry
- Automated robotic screening platform
- Diverse collections of small molecule libraries that include more than 500,000 approved drugs, natural product extracts, clinical candidates and diversity-focused screening libraries
- Unique array of biochemical and cell-based readers, including:
- High-content imaging
- Infrastructure for dispensing, dosing and washing assays in formats ranging from 6 to 1,536 wells
- Instrumentation for a full range of downstream applications to characterize findings in greater detail