Elucidating Mechanism of Action in Drug Invention: Using Stable Isotope Tracers to Unravel Biochemical Kinetics

ABSTRACT

Invention of a therapeutic begins by characterizing features that differentiate healthy and diseased states, this often presents as changes in the concentration of an analyte. Examples include elevated blood glucose in diabetes, high cholesterol in heart disease, and protein aggregation in neurodegeneration. Analyte concentrations reflect the (im)balance of synthetic and degradation rates, as such, aberrant biochemical kinetics drive the changes in endpoint concentration that define disease biology.

Therapeutics aim to reset the concentration of a disease marker via modulation of biochemical flux. This is easy to understand for drugs that directly target an enzyme in a pathway, but, perhaps less intuitive, this can be at the core of protein: protein interactions. Namely, stimulation of the insulin receptor activates the flux of several biochemical substrates (across multiple tissues), similarly, modulation of the PCSK9-LDL receptor interaction alters cholesterol trafficking. These examples underscore the importance of studying biochemical kinetics at a clinical level, we will discuss how stable isotopes can be used to link disease biology with drug screening and development. Examples will show how elucidating the mechanism of action (MoA) (i) has an immediate impact on enabling translation (IVIVc) in early discovery, (ii) can support biomarker plans and (iii) is used in pharmacokinetic-pharmacodynamic modeling to enhance our understanding of exposure-response and aid human dose prediction. MoA studies also impact modality selection, e.g. knowledge regarding target kinetics is needed when making decisions surrounding the development of a reversible inhibitor, irreversible covalent modifier, or an intervention that affects target levels.

BIOGRAPHY

I have a multidisciplinary background that spans fields of nutritional biochemistry, mass spectrometry, and mathematical modeling; my interests lie in explaining nutrient trafficking, including the interaction between dietary intake and disease states. I obtained a BS in Biology from St Michael’s College (VT) and then worked for ~ 3 years as a Research Assistant (Yale – we used GCMS-based metabolomics in clinical diagnostics, this all happened last century and metabolomics did not yet exist). I earned my PhD from Case Western Reserve Univ (OH), where I learned the fundamentals of isotope tracer methods. I spent ~ 2 years as a postdoc (Yale) where I applied tracer methods in novel models of insulin resistance and metabolic disease. I then moved back to Case Western where I was faculty for ~ 9 years – I have now been at Merck for the past ~ 15 years.