CHIPP for Target Engagement Analysis: All That and a Bag of CHIPPs

What is CHIPP – and why should you care?

The Momentum team has officially launched our new CHIPP service for target identification, deconvolution, and selectivity profiling. CHIPP – or chaotrope-induced protein precipitation and proteome profiling – is a novel technology that allows hundreds of compounds to be profiled in a scalable, automated, and label-free way. By significantly reducing the time and cost investment required to execute these experiments, CHIPP enables target engagement and selectivity profiling to be performed earlier in the drug discovery process. Rather than choosing a limited number of compounds to assess, researchers can interrogate several hundred primary screening hits in 96-well-plate format via CHIPP, then use the obtained information to prioritize compounds for further development. We believe that this new technology has the power to transform drug discovery workflows, ultimately helping more novel therapeutics progress into the clinical and towards FDA approval. Not convinced? Read on to learn more about why CHIPP is such a gamechanger!

What’s the point of target identification, deconvolution, and selectivity profiling?

CHIPP is a technology for the proteome-wide analysis of drug:target interactions that can be applied for target identification, deconvolution, and selectivity profiling. Target identification refers broadly to the process of identifying the protein or biomolecule that is bound by a drug or compound of interest, enabling it to exert some biological effect. The term ‘target deconvolution’ is used to refer to these efforts when the drug or compound was initially discovered through phenotypic screening. In a phenotypic screen, hits are identified by their effect on some biological phenotype (such as cell death, metabolic changes, or altered levels of a known biomarker) rather than by detecting their binding to relevant targets. Therefore, follow-up target deconvolution experiments must be performed to ascertain the molecular targets of these compounds and elucidate their mechanism of action. Selectivity profiling seeks to assess not only the intended binders of a drug or compound (on-targets) but also all other interactions (off-targets). Thorough knowledge of a compound’s off-target activity is critical ensuring the safety and efficacy of novel drugs during the drug development process.

How does CHIPP work?

A common strategy for the label-free identification of drug:target interactions involves progressively denaturing a sample and monitoring its stability. Because ligand binding affects the stability of a target protein, changes in stability compared to an untreated control can be taken to indicate target engagement. One existing approach – thermal protein profiling – subjects samples to increasing temperatures to induce thermal denaturation. In contrast, CHIPP involves the exposure of samples to increasing concentrations of chaotropic salts, which induce chemical denaturation through the disruption of hydrogen bonds. This approach enables stability analysis at physiological temperatures and is amenable to automation in 96-well-plate format using liquid handling platforms. Automation is further supported by the use of magnetic particles for protein precipitation; treated proteins can be readily captured and subjected to subsequent characterization via mass spectrometry. Mass spectrometry also supports proteome-wide analysis, meaning that all proteins in a sample can be simultaneously interrogated. The information obtained through mass spectrometry is used to generate denaturation curves and determine free folding energies for all analyzed proteins. Comparison of treated samples to untreated controls provides direct evidence of target engagement. Thanks to this combination of techniques and technologies, CHIPP is able to support the scalable, automated, and label-free analysis of drug:target interactions on a proteome-wide level and in a physiologically relevant context.

What are the benefits of CHIPP compared to other methods?

One key benefit of CHIPP compared to other methods for target identification and deconvolution is its throughput and scalability. Because CHIPP can be performed in 96-well-plate format to analyze hundreds of compounds in a single experiment, it can be used to triage primary screening hits and inform decision-making early in the drug development process. This offers a significant advantage compared to existing approaches, whose associated time and expense often force researchers to select only a few compounds for these profiling efforts. CHIPP is also label-free, providing relevant information on endogenous drug:target interactions without the confounding effects of tagging targets or compounds. In contrast to thermal protein profiling, CHIPP is performed at physiological temperatures, further enhancing the biological relevance of findings. Finally, CHIPP leverages the unmatched analytical capacity of mass spectrometry to analyze target proteomes with high depth and high sensitivity. This approach ensures that engaged targets are detected both accurately and comprehensively.

How can you leverage CHIPP for your drug discovery and development research?  

To learn more about how CHIPP could be integrated into your research workflow, send us a message! Our scientific team will schedule a meeting to discuss your project needs and explore how CHIPP (and any of our other services) could advance your drug discovery and development project.

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