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Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
DOI:
10.1038/nbt.2121
PMID:
22343925
Authors:
Elisabet
Wahlberg
(Structural Genomics Consortium, Karolinska Institutet)
,
Tobias
Karlberg
(Structural Genomics Consortium, Karolinska Institutet)
,
Ekaterina
Kouznetsova
(Structural Genomics Consortium, Karolinska Institutet)
,
Natalia
Markova
(Structural Genomics Consortium, Karolinska Institutet)
,
Antonio
Macchiarulo
(University of Perugia)
,
Ann-Gerd
Thorsell
(Structural Genomics Consortium, Karolinska Institutet)
,
Ewa
Pol
(GE Healthcare Bio-Sciences AB)
,
Åsa
Frostell
(GE Healthcare Bio-Sciences AB)
,
Torun
Ekblad
(Structural Genomics Consortium, Karolinska Institutet)
,
Delal
Öncü
(Actar AB)
,
Björn
Kull
(Actar AB)
,
Graeme Michael
Robertson
(University of Perugia)
,
Roberto
Pellicciari
(University of Perugia)
,
Herwig
Schüler
(Structural Genomics Consortium, Karolinska Institutet)
,
Johan
Weigelt
(Structural Genomics Consortium, Karolinska Institutet)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Nature Biotechnology
, VOL 30 (3)
, PAGES 283 - 288
State:
Published (Approved)
Published:
February 2012
Diamond Proposal Number(s):
6603
Abstract: Inhibitors of poly-ADP-ribose polymerase (PARP) family proteins are currently in clinical trials as cancer therapeutics, yet the specificity of many of these compounds is unknown. Here we evaluated a series of 185 small-molecule inhibitors, including research reagents and compounds being tested clinically, for the ability to bind to the catalytic domains of 13 of the 17 human PARP family members including the tankyrases, TNKS1 and TNKS2. Many of the best-known inhibitors, including TIQ-A, 6(5H)-phenanthridinone, olaparib, ABT-888 and rucaparib, bound to several PARP family members, suggesting that these molecules lack specificity and have promiscuous inhibitory activity. We also determined X-ray crystal structures for five TNKS2 ligand complexes and four PARP14 ligand complexes. In addition to showing that the majority of PARP inhibitors bind multiple targets, these results provide insight into the design of new inhibitors.
Journal Keywords: Binding; Catalytic; Computer; Crystallography; X-Ray; Enzyme; Humans; Poly(ADP-ribose); Protein; Tertiary; Small; Tankyrases
Subject Areas:
Medicine,
Biology and Bio-materials,
Chemistry
Instruments:
I03-Macromolecular Crystallography
Other Facilities: ID-29 at ERSF; Proteum X8 at Bruker; BL14-1, BL14-2 at BESSY
Added On:
27/03/2012 08:08
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)