assistant undergoing research training at Department of Immunology, Genetics and Pathology, Molecular tools; Research group Ulf Landegren
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Structural similarities in active sites of drug targets lead to risks of poor selectivity and unwanted side effects in rational drug design. There is a great need for more accurate techniques to monitor selective binding and correct localization of a candidate drug and its target interaction in healthy or pathological clinical specimen in the process of drug discovery in preclinical studies. In a first phase, we have developed very sensitively and specific in situ drug-target interaction detection methods TEMA (Target Engagement–Mediated Amplification), where target binding by DNA-linked kinase inhibitors were visualized and quantified in cells and tissues by rolling-circle amplification (RCA) and proxTEMA, using the proximity ligation assays mechanism. The methods serve to investigate selective target binding and correct localization of candidate drug in relevant clinical specimen during lead optimization in preclinical drug discovery. Another target engagement technology development effort is aimed to combine the cellular thermal shift assay (CETSA) with multiplex proximity extension assays (PEA) for quantitative drug proteins interaction analysis. Preliminarily we have developed a CETSA-PEA assay in cell extracts and a next aim is to apply this novel approach in consecutive fresh frozen samples of nucleated blood cells from leukemia patients before and after initiation of targeted therapy.
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