by Tonya Pekar Hart, Global Proteomics Market Manager, Thermo Fisher Scientific
Reaching the “undruggable” areas of the proteome is a priority ambition of the drug discovery and development community to progress treatments for diseases like cancer. Small molecule drugs that currently dominate the market only target a small fraction of proposed protein drug targets, with up to 80% previously considered “undruggable.” Advances in the discovery and development of molecular glues or TAC (Targeting Chimera)-based drugs have expanded the mechanism of action for therapeutic development to employ targeted protein degradation (TPD) using these covalent bivalent binding drugs.
The pharma and biopharma community have adopted a paradigm shift in drug discovery and development that leverages chemoproteomics and subsidiary workflows. Chemoproteomic profiling with mass spectrometry affords a holistic interrogation of the drug binding interactions in the proteome of the biological system. Recent advances in mass spectrometry now offer dramatic improvements in both proteome depth of detection and throughput of analysis to accelerate the drug discovery and development process. Research teams are now empowered to deploy targeted protein degradation techniques to guide the future of disease prevention, treatment, and more. And it starts with mapping the proteome.
The difficulties of reaching the proteome for cancer drugs
Cancer development can be caused by gene mutations or alterations, which result in the proliferation of proteins stemming from oncogene activation(s) that turn healthy cells into cancer cells. While traditional small molecule drugs target some of these proteins, not all protein targets are accessible using conventional treatment approaches.
There are major differences between small and large molecule drugs, such as biologics, related to size, structure, complexity, and how they interact within the body. Small molecule drugs are usually chemically synthesized, while protein-based drugs are often derived from biological sources. Small molecule drugs confer several advantages, as they can be administered orally, are more cell permeable, can be easier to manufacture, and have more predictable pharmacodynamic properties.
Previously, drug discovery with small molecules relied extensively on reversible protein drug binding, but there were associated risks and challenges when the target proteins lack pockets or surfaces to bind to. However, targeted protein degradation is revolutionizing the field by utilizing molecular glues or TACs to induce the degradation of proliferated or dysfunctional proteins. These small molecule drugs simultaneously target both proteins of interest and molecular machinery that facilitates the degradation of that protein using the body’s natural processes to eliminate such dysfunctional proteins. Small molecule drugs have additional advantages, including the ability to target intracellular processes that large molecule drugs might not be able to reach effectively, which is making it easier to target and “drug” new areas of the proteome. Due to the success of small molecule drugs thus far, scientists are now exploring more of these approaches to address the "undruggable" areas. Chemoproteomic profiling and mass spectrometry-based methods are accelerating discovery and characterization during development.
Chemoproteomics growing prevalence
Chemoproteomics plays a crucial role in advancing drug development efforts for numerous reasons. Direct profiling of the proteome enables the study of the interactions between small molecules and proteins more comprehensively than ever before. By applying mass spectrometry-based methods, scientists can now map and understand the interactions between small molecule drugs and proteins within complex biological systems to better understand mechanisms of action and assess drug specificity with a holistic perspective. Chemoproteomic profiling allows unbiased assessment of drug binding in the biological system. It can identify and validate binding to desired proteins of interest while simultaneously assessing ‘off-target’ binding (those proteins not meant to be targeted, which could produce undesired side effects). This allows for direct measurement of the selectivity and safety of the drug.
One of the most commonly mutated proteins in cancer proliferation is the KRas protein, which serves as an example that was previously difficult to target due to unidentifiable pockets to bind to. However, in recent years, as technology like mass spectrometry and research advances, scientists have been able to characterize KRas for cancer diagnosis and unlock insights into how to target it. Breakthroughs like this demonstrate the potential of leveraging chemoproteomic profiling to enable scientists to target areas of the proteome previously thought improbable.
Chemoproteomic profiling can allow for multiple interrogations of drug profiles. It can identify and validate target proteins, elucidate binding sites and mechanisms of action, and simultaneously assess the selectivity of a drug. It can also map protein-protein interactions within cells or tissues, which has been useful for identifying potential therapeutic targets in complex networks and then to profile developed therapeutics. The key advantages of chemoproteomic approaches are that they are holistic and offer a direct assessment of the biological system being studied and the impact drug targets have on those systems.
The future of drug discovery and development
Chemoproteomic profiling techniques are actively being employed to identify and characterize protein targets of small molecules in cancer cells. For example, Scripps Research’s recent study features a new process of enhanced mapping of small-molecule binding sites in cells. Their work reveals new opportunities for therapeutic intervention and discovery in human cells. Additionally, chemoproteomics has been pivotal for investigating therapeutic interventions for autoimmune diseases, such as rheumatoid arthritis, where the immune system mistakenly attacks the body’s tissues. Armed with in-depth knowledge of specific and complex protein targets and pathways, researchers can best explore the development of targeted therapies for mitigating autoimmune responses and creating effective therapeutics for cancer.
The role of mass spectrometry has already made a significant impact on drug discovery and development. It’s likely that 90% of major players in the pharma/biopharma industry will employ some form of chemoproteomic profiling techniques into their development process. Such techniques have become predominant due to the approach's unbiased and holistic perspective, which can further help assess the dynamics of drug dosing responses during the development process. Adoption has accelerated in the past five years, partially driven by the advancement in the performance of modern mass spectrometers. The development of more powerful and sensitive instrumentation allows for deeper characterization of the proteome with higher throughput. Thus, scientists will be able to more comprehensively assess the impact of drug dosing, which will improve the understanding of the drug profile to confirm efficacy, selectivity, and safety. Anticipated advancements in early detection, personalized therapies, and a deeper understanding of the biology of diseases are on the horizon.
Moving forward, chemoproteomics enabled by mass spectrometry will build much of the foundation for therapeutic research and development. The rise in prevalence highlights the impact technology advancements can have on accelerating breakthroughs in the industry.