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“Exploring the regulatory apparatus of Bruton’s tyrosine kinase – a drug target for B-cell cancers”

Bio: Amy Andreotti is the Roy J. Carver Chair in Biochemistry and a University Professor at Iowa State University. She joined the faculty of the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology in 1997 after earning her PhD in Chemistry at Princeton University and completing a postdoctoral training period in the Chemistry Department at Harvard University where she was a Science Scholar at the Bunting Institute of Radcliffe College. Her work explores the mechanisms of kinase regulation during cell signaling with an emphasis on the immune specific TEC family of non-receptor tyrosine kinases. Currently Amy serves on the National Advisory Committee for the Pew Biomedical Scholars Program, is a senior editor at eLife, and is a member of the committee overseeing inclusion of kinases in the IUBMB enzyme classification system.

Abstract: To date, over 70 small molecule kinase inhibitors have been approved by the US Food and Drug Administration (FDA) for human use. One such inhibitor, ibrutinib (IMBRUVICA®), targets the B-cell tyrosine kinase, Bruton’s tyrosine kinase (BTK). Ibrutinib covalently binds to the BTK ATP-dependent kinase active site, a common site of action of kinase inhibitors. Ibrutinib is currently indicated for the treatment of chronic lymphocytic leukemia (CLL) in addition to other B cell lymphomas/leukemias. Since an increasing number of CLL patients treated with ibrutinib develop drug resistance through mutation of BTK, second generation inhibitors are now in the pipeline. To advance our ability to target BTK in the context of disease, we are using a range of approaches (NMR spectroscopy, hydrogen-deuterium exchange mass spectrometry, biochemical assays) to study the effects of BTK inhibitors on the full length BTK protein, the mechanism of resistance mutations, and the allosteric regulation of BTK activity. We find surprising differences between the active site directed drugs and are uncovering the unique mechanistic details that control BTK function in the resting versus activated B cell. 

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