Webinar on Structure-based design & development of inhibitors of the Tankyrases, drug targets in cancer and diabetes

Prof. Dr. Michael D Threadgill (MA PhD DSc FRSC CChem) Fellow Royal Society of Chemistry

Abstract: Tankyrases (TNKSs) are members of the poly(ADP-ribose)-polymerase (PARP) family of seventeen enzymes that use NAD+ as a source of ADP-ribose units to attach to target proteins as a regulatory post-translational modification. Target proteins of the two tankyrases include telomere repeating binding factor-1 (TRF1), nuclear mitotic apparatus protein (NuMA) (essential for separation of chromatids in cell division) and axin (a major component of Wnt / b-catenin signalling). Inhibition of TNKSs is reported to lead to decreased proliferation of cancer cells. The axin−TNKS−KIF3A complex is needed for insulin-stimulated translocation of GLUT4 to the cell membrane. Insulin-regulated amino-peptidase (IRAP) is also a binding partner and target protein of TNKSs. Thus inhibition of TNKSs should enhance insulin-stimulated exocytosis of GLUT4, leading to increased uptake of glucose in peripheral tissues, important in the management of diabetes.
This lecture will describe the story of how my group, with important external collaborations, explored the NAD+-binding site of the tankyrases through design, synthesis and biochemical evaluation of several series of isoquinolin-1-ones, quinazolin-4-ones, naphthyridinones, pyridopyrimidinones and related compounds. Crystal structures of several of these inhibitors, along with Structure-Activity Relationship studies, allowed detailed understanding of the shape and properties of the nicotinamide-binding pocket. NAD+ is also a substrate for many other enzymes in mammalian cells, including oxidoreductases and the other PARPs; thus the selectivity of inhibitors is important. These studies also led to an understanding of the structural basis for selectivity of inhibition of tankyrases vs. PARP1. Further elaboration of the core structure culminated in identification of two “dual-site” inhibitors binding at both the nicotinamide-binding pocket and at the adenosine-binding pocket. These final designed inhibitors showed exquisite potency (IC50 vs. tankyrase-2 100 pM) and selectivity (65000× selective for tankyrase-2 vs. PARP1).
Target Audience: This webinar is open to academicians, scientists, and general public from all the member OIC states and beyond.
Research Interest of speaker: The research focus of the Threadgill group is drug design and delivery. We work on the application of medicinal chemistry (structure-based drug design, chemical synthesis, biochemical and cell biological evaluation) to developing new cancer treatments. Where the biochemistry of other diseases is similar (haemorrhagic shock, stroke, myocardial infarction, etc.), our work has branched out into these areas. We also research new synthetic methods in organic heterocyclic chemistry. Collaborations in Bath, Aberystwyth, Finland, India and Poland are important to our work.

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