2. Academic Validation
  3. Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14

Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14

  • ACS Chem Biol. 2017 Nov 17;12(11):2866-2874. doi: 10.1021/acschembio.7b00445.
Marion Schuller 1 2,  Kerstin Riedel 3,  Ian Gibbs-Seymour 4,  Kristin Uth 1,  Christian Sieg 1,  André P Gehring 3,  Ivan Ahel 4,  Franz Bracher 3,  Benedikt M Kessler 2,  Jonathan M Elkins 1,  Stefan Knapp 1 5 6
Affiliations

Affiliations

  • 1 Structural Genomics Consortium (SGC), Nuffield Department of Clinical Medicine, University of Oxford , Oxford, OX3 7DQ, United Kingdom.
  • 2 Target Discovery Institute (TDI), Nuffield Department of Clinical Medicine, University of Oxford , Oxford, OX3 7FZ, United Kingdom.
  • 3 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University of Munich , 81377 Munich, Germany.
  • 4 Sir William Dunn School of Pathology, University of Oxford , South Parks Road, Oxford, OX1 3RE, United Kingdom.
  • 5 Institute of Pharmaceutical Chemistry and Buchmann Institute for Molecular Life Sciences, Goethe University , 60439 Frankfurt, Germany.
  • 6 German Cancer Network (DKTK), Frankfurt/Mainz site , Frankfurt am Main, Germany.
PMID: 28991428 DOI: 10.1021/acschembio.7b00445
Abstract

Macrodomains are conserved protein interaction modules that can be found in all domains of life including in certain viruses. Macrodomains mediate recognition of sequence motifs harboring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in Cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterization of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallization of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prevents its localization to sites of DNA damage.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108708
    99.97%, PARP14抑制剂
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