Speaker: Lauren Kueffer
Title: Harnessing the Regulatory Interactions Within BTK for the Development of a Small Molecule Screen
Abstract: Bruton’s Tyrosine Kinase (BTK) is a critical kinase playing a role in B-cell development and maturation. From N- to C-terminus it is composed of a plekstrin homology domain (PH), a Tec homology domain (TH), a Src homology-3 domain (SH3), a Src homology-2 domain (SH2), and a kinase domain. BTK is overactive in many B-cell lymphomas and several inhibitors are in various stages of clinical trials. Ibrutinib is the only inhibitor that has been approved for use in patients with mantle cell lymphoma and chronic lymphocytic leukemia. However, patients have been found to develop resistance to ibrutinib and the drug can also inhibit another Tec family kinase, ITK. So, there is interest in targeting BTK allosterically to achieve more specificity and to be used in combination with current inhibitors. The first aim of this research is to exploit an autoinhibitory interaction within BTK between the PH and kinase domains and develop a cellular system which we can use to screen for small molecules influencing this interaction. Structural studies with these hits will need to be pursued. The nearest full-length structure of BTK is a domain swapped dimer of SH3-SH2-Kinase portion with the domain swapping occurring at the SH2 domain. In order to make a more stable monomeric state, stabilizing the autoinhibitory contact between these domains will be strengthened. By creating a more stable monomer, the binding site of novel small molecule hits can be determined.