Abstract
Abstract Targeted therapies are dependent on adequate occupancy and target engagement to reach their efficacy measure. Yet, more than half of novel candidate drugs entering clinical trial stage fail before proof of concept is achieved. Inadequate target engagement is often at the root cause of these failures. Therefore, we have developed a versatile label-free method to quantify the target engagement of drugs on their native physiological relevant targets. The method is validated in multiple sample matrices, using different technical platforms to allow studies of target engagement from bench to bedside: in living cells and tissue from rodents and man. CETSA(®) is a patented biophysical method measuring the thermal stability of drug target proteins and the shift induced by their ligands. By quantifying the melting temperature and shift induced by the ligand we can quantify the potency of target engagement. This potency determination allows filtering of candidate drugs by their ability to engage the target in its physiologically relevant form, in relevant sample formats such as intact cells or tissue. We present several applications of the method and the utility in preclinical in vitro studies and translation to in vivo systems. In addition, new powerful detection formats are being evaluated and will be presented. The utility and value of the CETSA(®) method enabling preclinical development of novel drugs is substantiated by the examples included here. We show the value of the method both for compound/drug profiling, for target profiling and for unbiased drug profiling on whole proteomes in response to drug treatments. Such datasets can be generated from in vitro systems to clinical samples and may reduce the high attrition rate in proof of concept studies by facilitating the discovery, development and evaluation of novel drugs. Citation Format: Jakob Karen, Catrine Sioberg, Nancy Dekki Shalaly, Daniel Martinez Molina. Physiologically relevant target engagement using the cellular thermal shift assay (CETSA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4024. doi:10.1158/1538-7445.AM2017-4024
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