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Title: Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1]
  1. Univ. Health Network, Toronto, ON (Canada)
  2. Univ. Health Network, Ontario (Canada); Univ. of Toronto, Toronto, ON (Canada)
  3. Univ. Health Network, Toronto, ON (Canada); Univ. of Toronto, Toronto, ON (Canada)
Publication Date:
OSTI Identifier:
1162303
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Acta Crystallographica. Section D: Biological Crystallography (Online)
Additional Journal Information:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography (Online); Journal Volume: 70; Journal Issue: 10; Journal ID: ISSN 1399-0047
Publisher:
International Union of Crystallography
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES cancer; poly(ADP-ribose) polymerase; TNKS2; structure-based drug discovery; structural biology