The search for new and better drugs requires significant innovation. One of the opportunities for drug discovery is a better understanding of the parts of the human proteome that have been hidden from traditional approaches. The development of more powerful mass spectrometry instruments and methods has enabled exploration of these unreachable areas of the human proteome.
Here, Tonya Pekar Hart, global proteomics market manager for Thermo Fisher Scientific, shares more on this approach to drug discovery
Q: What is a useable definition of unreachable areas of the human proteome?
A: Unreachable areas of the human proteome refer to protein drug targets known to be involved in disease processes, particularly in conditions like cancer, which had proven difficult to target effectively with existing therapeutic approaches, such as small molecule drug inhibitors or biologic drugs. These targets often possess characteristics, such as poorly defined binding sites, involvement in complex protein interactions or challenging to access cellular locations, which made it challenging to engage with drugs to produce a desirable therapeutic outcome. Some studies suggest that up to 85 percent of known protein drug targets were considered undruggable.
Q: Why is gaining a better understanding of the unreachable areas important?
A: Understanding the unreachable areas of the human proteome is crucial because it could accelerate drug discovery and development to advance treatments for diseases like cancer. Small-molecule drugs that currently dominate the market—up to 90 percent of all drugs sold worldwide—only target a fraction of the many proteins involved in various diseases. The development of new therapeutic approaches, such as those that leverage targeted protein degradation pathways with PROTAC or molecular glue drug modalities, enable the opportunity to target these previously undruggable proteins through new mechanisms of action.
Development in this space allows for novel treatments that could also address issues with treatment resistance, allow for more precise and personalized therapies (precision medicine), and help improve our understanding of disease biology.
Q: What is required to probe these unreachable regions?
A: Traditionally, small-molecule drugs were limited by their reliance on reversible protein drug binding and inhibition of activity, which is problematic when target proteins lack accessible or well-defined binding activity pockets. Targeted protein degradation (TPD) is a rapidly emerging therapeutic approach which leverages the body’s own mechanisms to remove disease-causing proteins from cells through degradation, rather than inhibiting their activity. They function to bind both accessible areas of the protein and cellular machinery that triggers natural degradation of that protein.
Q: What is chemoproteomics, and why is it important?
A: Chemoproteomics is a multidisciplinary field that leverages proteomics approaches enabled by mass spectrometry to study the interactions of small molecule chemical probes (i.e. drugs) and proteins in living systems. The approach allows for unbiased interrogation to assess whether drugs bind desired or undesired (side effects) protein targets. This allows a more holistic and simultaneous understanding of disease mechanisms and drug specificity, which can inform a drug's safety and selectivity to accelerate drug discovery and development.
The holistic and direct nature of chemoproteomics profiling is pivotal in studying biological systems and drug targets' impact for many diseases, not just cancer. The same platform has been utilized to aid development of therapeutic interventions for autoimmune diseases like rheumatoid arthritis, where the immune system may mistakenly attack the body's tissue or cells.
Our team estimates that 90 percent of major biotech and pharmaceutical companies will ultimately deploy chemoproteomic workflows and profiling techniques into their discovery and development processes.
Q: How does chemoproteomics accelerate drug discovery?
A: Chemoproteomic profiling allows for direct measurement of drug binding interactions within biological systems to elucidate the mechanisms of actions of drugs and validate their intended targets. This is critical for prioritizing drug candidates or protein targets and guiding medicinal chemistry efforts for further development. The ability to assess binding of unintended targets that could cause deleterious side effects early in the drug discovery process prevents costly pursuit of candidates that could fail later in drug development due to safety concerns or poor efficacy.
Q: What are the key challenges to doing chemoproteomics?
A: Accurately identifying and quantifying the protein targets of chemical probes (drugs) within biological systems can be technically challenging. Proteomics analysis techniques leveraging mass spectrometry must be sensitive and robust enough to detect low-abundance proteins and accurately quantify changes in protein abundance or modification states induced by chemical probes. With targeted protein degradation, it becomes even more important to assure analytical tools offer both accuracy of measurement and sensitivity to detect protein-drug targets as those proteins “degrade” to lower levels in the cell.
Sufficient bioinformatic tools are required to process and manage large, comprehensive but complex proteomics data sets. Biological systems are inherently complex, with thousands of proteins interacting dynamically within communication networks or pathways. Understanding the functional significance of the protein targets identified by chemoproteomics within physiology and disease processes requires integration and interpretation of complex data.
Validation of discovered targets across biological systems and laboratories are critical challenges. Robust data collection and validation experiments are necessary to confirm the biological significance and accuracy of results.
Q: What breakthroughs have enabled chemoproteomics?
A: Several breakthroughs have enabled the advancement of chemoproteomics. The development of chemical biology techniques, such as click chemistry and biorthogonal chemistry, have enabled the synthesis of chemical probes (drugs) with functional groups that covalently bind target proteins within complex biological systems.
Advances in the performance of mass spectrometry instrumentation and analytical workflows have revolutionized proteomic analyses, allowing for the sensitive and accurate detection and quantification of proteins within complex biological systems. State-of-the-art mass spectrometry platforms, coupled with innovative data acquisition and analysis algorithms, enable comprehensive profiling of protein targets and modifications induced by chemical probes across the entire proteome in one study. The approach offers unbiased and comprehensive insights.
The development of bioinformatic tools has also been crucial to enable scientists to identify protein candidates, infer biological insights and integrate information from multiple experimental sources.
Continued innovation and collaboration in the field of chemoproteomics are expected to drive further breakthroughs and accelerate the development of novel therapeutics for various diseases.