Development of preclinical HTS for discovery of drugs modulating apoptosis

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

Current preclinical high-throughput drug screening methods are time-consuming and expensive. Moreover, most of the candidates generated during screenings turn out to be invalid after further testing in animal models. To overcome these limitations, efforts are now being made to develop noninvasive, highly sensitive and cost-effective imaging tools for monitoring and early detection of drug efficacy in single cells and in vivo. Activatable imaging probes are designed to amplify or boost fluorescence signals in response to recognition of specific biomolecular interactions. We developed various protease-activatable systems for imaging and diagnostic applications by using advanced nanobioconjugation chemistry with fluorophores, peptides, polymers and metals. In this proposal, we plan to expand those research findings to a novel preclinical drug screening system for the rapid characterization of apoptosis-related drug candidates. Because the most effective anticancer therapeutics mediate apoptosis cascades, real time screening methods to detect the progression of apoptosis at the molecular level in single cells in vitro and in vivo would significantly improve the understanding of intracellular apoptotic signal mechanisms and could assist the clinical monitoring and screening of apoptosis-related drug efficacy. We will develop advanced screening technologies that can be applied in cell-based high-throughput and in vivo drug screening for next generation drugs targeting apoptosis. Different types of activatable imaging systems that target crucial apoptosis mediators, caspases, will be developed and optimized for in vitro and in vivo applications. By targeting a crucial apoptosis mediator, the early stage of apoptosis can be readily monitored, imaged and analyzed in a rapid and efficient fashion. Selected screening systems will be validated in various experimental models of tumor apoptosis. Standard in vitro and in vivo drug screening methods will be drafted. Overall, this system is expected to significantly reduce time and costs associated with drug screening tests in animals. Our aim is to develop fully translatable preclinical screening systems for drug discovery targeting apoptosis. Success of the proof-of-concept illustrated in this initiative will allow for widespread preclinical and clinical applications.