Emerging applications of kinetic biomarkers in preclinical and clinical drug development.
The cost of drug discovery and development is increasing, while the rate of new drug approvals is declining. In contrast to major technological advances with in silico and in vitro screening tools, there have been almost no advances in the tools available for establishing the actions of agents in the complex biochemical networks characteristic of fully assembled living systems. The resulting poor capacity to predict clinical response underlies the high attrition rate of leads at every step of drug development. A potential solution would be provided by kinetic biomarkers (in vivo measurement of fluxes though the key pathways that drive disease processes and therapeutic response). Novel approaches using stable isotope labeling with mass spectrometric analysis have recently emerged for measuring molecular kinetics relevant to drug targets with some applications to drug development. This review discusses the general principles of kinetic biomarkers, providing examples where kinetics have generated meaningful insights into drug activity and highlighting areas where the application of kinetic biomarkers may be particularly useful for future drug discovery and development. Stable isotope mass spectrometric technologies may provide a parallel efficiency for converting molecules into approved drugs with sufficient throughput and reproducibility to maintain pace with the modern engine for generating leads.
Turner
Scott M
SM
KineMed Inc, Emeryville, CA 94608, USA. sturner@kinemed.com
Hellerstein
Marc K
MK
D000818:Animals; D015415:Biomarkers; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011237:Predictive Value of Tests
D015415:Biomarkers; D004364:Pharmaceutical Preparations