Journal ArticleDOI
Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
Elisabet Wahlberg,Tobias Karlberg,Ekaterina Kouznetsova,Ekaterina Kouznetsova,N. Markova,N. Markova,Antonio Macchiarulo,Ann-Gerd Thorsell,Ewa Pol,Åsa Frostell,T. Ekblad,Delal Öncü,Björn Kull,Graeme M. Robertson,Roberto Pellicciari,Herwig Schüler,J. Weigelt +16 more
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TLDR
Evaluated small-molecule inhibitors of poly-ADP-ribose polymerase (PARP) family proteins showed that the majority of PARP inhibitors bind multiple targets, providing insight into the design of new inhibitors.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.read more
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Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
Junko Murai,Shar Yin N. Huang,Benu Brata Das,Amelie Renaud,Yiping Zhang,James H. Doroshow,Jiuping Ji,Shunichi Takeda,Yves Pommier +8 more
TL;DR: This study shows that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA, providing a new mechanistic foundation for the rational application ofPARP inhibitors in cancer therapy.
Journal ArticleDOI
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Daniel Martinez Molina,Rozbeh Jafari,Marina Ignatushchenko,Takahiro Seki,E. Andreas Larsson,Chen Dan,Lekshmy Sreekumar,Yihai Cao,Yihai Cao,Pär Nordlund,Pär Nordlund +10 more
TL;DR: This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins and validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues.
Journal ArticleDOI
New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs.
Bryan A. Gibson,W. Lee Kraus +1 more
TL;DR: This work has shown that the activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation (PARylation) they ultimately promote changes in gene expression, RNA and protein abundance, and the location and activity of proteins that mediate signalling responses.
Journal ArticleDOI
HemI: a toolkit for illustrating heatmaps.
TL;DR: An easy-to-use tool named HemI (Heat map Illustrator), which can visualize either gene or protein expression data in heatmaps and provides multiple clustering strategies for analyzing the data.
Journal ArticleDOI
Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib
Junko Murai,Shar-yin N. Huang,Amelie Renaud,Yiping Zhang,Jiuping Ji,Shunichi Takeda,Joel Morris,Beverly A. Teicher,James H. Doroshow,Yves Pommier +9 more
TL;DR: BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP–DNA complexes and is also approximately 100-fold more cytotoxic than olaparib and rucaparIB in combination with the DNA alkylating agents methyl methane sulfonate and temozolomide.
References
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Journal ArticleDOI
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Hannah Farmer,Nuala McCabe,Christopher J. Lord,Andrew Tutt,Andrew Tutt,Damian A. Johnson,Tobias B. Richardson,Manuela Santarosa,Krystyna J. Dillon,Ian Hickson,Charlotte Knights,Niall M. B. Martin,Stephen P. Jackson,Graeme C. M. Smith,Alan Ashworth +14 more
TL;DR: BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage.
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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Helen E. Bryant,Nilklas Schultz,Huw D. Thomas,Kayan M. Parker,Dan Flower,Elena Lopez,Suzanne Kyle,Mark Meuth,Nicola J. Curtin,Thomas Helleday,Thomas Helleday +10 more
TL;DR: It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
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Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Peter C.C. Fong,D. S. Boss,Timothy A. Yap,Andrew Tutt,Peijun Wu,Marja Mergui-Roelvink,Peter S. Mortimer,Helen Swaisland,Alan Lau,Mark J. O'Connor,Alan Ashworth,James Carmichael,Stan B. Kaye,Jan H.M. Schellens,Jan H.M. Schellens,Johann S. de Bono +15 more
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Journal ArticleDOI
The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability
TL;DR: Differential scanning fluorimetry (DSF) is a rapid and inexpensive screening method to identify low-molecular-weight ligands that bind and stabilize purified proteins.
Journal ArticleDOI
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
Andrew Tutt,Mark E. Robson,Judy Garber,Susan M. Domchek,M. William Audeh,Jeffrey N. Weitzel,Michael Friedlander,Banu Arun,Niklas Loman,Rita K. Schmutzler,Andrew M Wardley,Gillian Mitchell,H. M. Earl,Mark Wickens,James Carmichael +14 more
TL;DR: Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.