Post-Translational Modifications (PTMs) in Drug Discovery & Development

Post-translational modifications (PTMs) play critical regulatory roles in virtually every biological context, modulating the activity, localization, interactions, and stability of target proteins. By exploiting different PTMs (or combinations thereof), the functionality of a single protein can be altered to respond effectively to diverse cellular conditions or stimuli. These modifications – which include phosphorylation, acetylation, ubiquitination, glycosylation, and methylation – can be critical to drug discovery and development efforts. Many drugs function by inhibiting enzymes that deposit, recognize, or remove PTMs, thereby altering downstream signaling and activity. Still other drugs are affected by PTMs to their target protein, with binding ability or affinitydictated by the target’s PTM state. More generally, PTMs are key components of cellular signaling, and their evaluation can provide valuable insight into pathway activity or inhibition. In this blog post, we’ll explore what PTMs are, why they are so important in drug discovery and development research, and how you can integrate PTM analysis into your research workflows.

What are PTMs?

Post-translational modifications, or PTMs, are chemical alterations made to proteins after their synthesis. While the most common type of PTM is the addition of a small functional group (such as a phosphate group, ubiquitin, or sugar molecule) to the target protein, PTMs also encompass phenomena such as proteolytic cleavage, which involves the cleavage of a peptide bond. Typically, PTMs serve to modulate the function of a protein, activating or deactivating its enzymatic activity. However, PTMs can also modify the localization of a target protein, alter its ability to interact with other proteins or with small-molecule drugs, or trigger the protein’s degradation.

Estimates of the number of unique PTM types range from >200 to >650, highlighting the sheer diversity of potential modifications. Well-characterized PTMs include acetylation, glycation, glycosylation, hydroxylation, lipidation, methylation, S-nitrosylation, SUMOylation, phosphorylation, and ubiquitination. Some PTMs are reversible; for example, kinase enzymes act to phosphorylate targets, while phosphatase enzymes remove these phosphate groups to restore the original activity state. In contrast, proteolytic cleavage is an irreversible process that permanently alters protein status. Taken as a whole, PTMs represent a critical layer of biological regulation that substantially expands the diversity of the proteome and enables cells to respond effectively to perturbations, stimuli, and developmental transitions.

Why are PTMs important in drug development?

PTMs play central roles in drug discovery and development, as well as in disease biology. A range of disease states – including many cancers – are driven or characterized by dysregulation of PTMs. For example, hyperphosphorylation of the tau protein is a key signature of Alzheimer’s disease and has been proposed to play a causative role in the formation of tau filaments. In such cases, global or targeted analysis of PTMs can support biomarker identification and provide valuable insight regarding disease mechanisms.

PTMs can also provide a direct avenue for therapeutic intervention, with researchers targeting proteins that read, write, or erase relevant PTMs to ameliorate disease processes. Several HDAC inhibitors (including vorinostat, romidepsin, belinostat, and panobinostat) have been FDA-approved for the treatment of various cancers. These compounds act to inhibit histone deacetylases, or enzymes that remove acetyl PTMs from histone proteins. By pharmacologically inhibiting HDAC activity, these treatments seek to mitigate disruptions in transcriptional regulation associated with oncogenesis.

In other cases, PTM induction can serve as a therapeutic modality in and of itself. Most targeted protein degraders act by recruiting ubiquitinating enzymes to a target protein; the target protein is ubiquitinated and subsequently subjected to proteasomal degradation. Even more broadly, recent research has demonstrated that a target’s PTM state can affect its ability to engage small molecules, making PTM analysis crucial to any comprehensive drug development program.

What services does Momentum offer for PTM analysis?

At Momentum, we offer a range of services to support PTM analysis. For comprehensive characterization of PTMs, we offer DecryptM, a concentration-resolved workflow that enables global profiling of PTM changes in response to drug treatment or other perturbations. This technology supports a range of drug discovery applications, including pathway engagement analysis and MoA studies. Our SignalingScout™ technology enables proteome-wide profiling of dynamic phosphorylation events across hundreds to thousands of cell or tissue samples, regularly detecting >30,000 phospho-sites across >8,000 proteins. With this approach, researchers can gain valuable insight into the differences in cell signaling between cell types, in a disease state, or following drug treatment. UbiScout™ is proteomic technique that comprehensively profiles ubiquitination sites and is particularly well-suited for the development of molecular glue degraders and other targeted degrader modalities. We can also perform customized analyses targeted to specific modifications or protein targets, providing flexible support to unique experimental applications.

Summary

Post-translational modifications are critical regulators of protein activity, localization, interactions, and more. As such, they play a central role in any investigation of disease biology, as well as in the drug discovery and development process. At Momentum, we are proud to offer a range of services to support PTM profiling, leveraging the power of mass spectrometry to enable comprehensive, global analysis of post-translational modifications in diverse sample types. To learn more about our offerings – or to kick off your PTM analysis project – send a message to our team.

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