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)