Role and potential of MS methods in pharma research
Emerging evidence from academic and industrial research creates hypotheses for novel therapeutic intervention. To produce as well as to test these hypotheses, analytical methods are key.
Electrospray mass spectrometry (ESI-MS) and its coupling to liquid chromatography (LC/MS) has revolutionized biochemical and biomedical research in the past twenty years – in pharma research mainly in the fields of biochemistry, pharmacokinetics and drug metabolism (DMPK). Big pharma has adopted the technology and there are many competent third party labs which allow outsourcing of the activities. But:
Mass spectrometry is underexploited in drug discovery
Although the technology is quite mature, it is not used appropriately in early discovery – mainly for the following reasons:
- In contrast to early development, discovery distributes limited resources to many projects and is reluctant to adopt investment intensive “high-tech” methods or to support common central facilities.
- Current biology training presents mass spectrometry as a tool for protein identification while the applications for biophysics, quantification and metabolic analysis are neglected.
- In consequence the discovery applications have to be developed by the early development department where they have low priority.
Make Mass Spectrometry available to your project biology! There are competent and flexible service labs for any specialization. Let smv3.ch establish and manage the collaboration.
Applications with potential:
Compound screening and hit qualification (especially enzyme targets)
Some years ago a “medium” throughput MS based instrument has been commercialized and is used successfully by most big pharma companies and also some CRO labs. The advantage over conventional screening methods based on optical detection is that the original biochemical substrates and products can be detected (label free method) and therefore the results are considered to be more relevant. Secondly, MS allows the simultaneous detection of multiple analytes and is more specific. The disadvantages are the lower throughput, the limited compatibility with buffers and detergents and of course the technical complexity which requires qualified operators.
Direct and affinity chromatography based methods are used increasingly to validate hits because they allow an identity confirmation of the binder/substrate and can show eventual biotransformations.
Latest results of renowned research groups make membrane proteins like GPCR’s and transporters accessible and promise a dramatic increase in sample throughput.
Target response biomarkers
Projects having a translational biochemical readout progress faster and safer. It is – complementing the DMPK data – extremely useful for
- the proof of principle (entry into portfolio)
- the extrapolation of the doses in the early safety studies (clinical candidate selection)
- the determination of target occupancy (all stages)
Studies from Astra-Zeneca demonstrate that projects with such activity biomarkers progress faster and can be terminated for clearer reasons than others . At Roche we had an impressive analytical portfolio ranging from neurotransmitters over hormones to lipokines, several classes of lipids and other intermediates of the energy metabolism. Projects using LC/MS for biomarker analysis were clearly less challenged than others.
The method is particularly suited for metabolic and cardiovascular diseases, neurology, ophtalmology, renal diseases and infectious diseases. In terms of targets, enzymes are most suited, followed by transporters and GPCR’s with metabolic effect.
Biomarker discovery and metabolic profiling
Although it is an extremely valuable tool for phenotypic drug discovery and disease biomarker research the application of LC/MS to metabolic profiling has a somewhat bad reputation. To my opinion it comes from the facts that it is pretty expensive but also that the success factors of -omics studies are too manifold and very interdependent.
In phenotypic projects or in search for off-target effects the protein interactome of the ligand can be determined with various mass spectrometry based methods. Those studies are expensive and since the success depends a lot from the individual project situation, a tight scientific interaction is necessary during planning and execution.
Make a step forward
In my functions within the Mass Spectrometry group of Roche’s Discovery Technology department I had the unique chance to be part of a team of competent specialists who pioneered with me many of the the above mentioned applications. The project team memberships in the past ten years provided invaluable insights into the “mechanics” of drug discovery projects. Contact me for:
- Development of translational biomarkers in early discovery, using external resources
- LCMS courses
- Setup of collaborations
- Introduction of biophysical MS methods
- LCMS instrument evaluation
 Cook, D., D. Brown, R. Alexander, R. March, P. Morgan, G. Satterthwaite and M. N. Pangalos (2014). “Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework.” Nat Rev Drug Discov 13(6): 419-431.