Design and discovery of 3-aryl-5-substituted-isoquinolin-1-ones as potent tankyrase inhibitors

Elliott, Richard; Jarvis, Ashley; Rajasekaran, Mohan B.; Menon, Malini; Bowers, Leandra; Boffey, Ray; Bayford, Melanie; Firth-Clark, Stuart; Key, Rebekah E.; Aqil, Rehan; Kirton, Stewart B.; Niculescu‐Duvaz, Dan; Fish, Laura J.; Lopes, Filipa; McLeary, Robert; Trindade, Inês B.; Vendrell, Elisenda; Munkonge, Felix M.; Porter, Rod A.; Perrior, Trevor; Springer, Caroline J.; Oliver, Antony W.; Pearl, Laurence H.; Ashworth, Alan; Lord, Christopher J.

doi:10.1039/c5md00210a

Cited by 11 publications

(14 citation statements)

References 17 publications

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“…The role of PARP1, 2, and 3 in the DDR provided the rationale for the discovery and development of clinical PARP inhibitors. In addition, tankyrase inhibition can suppresses constitutive Wnt signaling 4 , which has led to the discovery of a series of small molecule TNKS/TNKS2 inhibitors 7 8 . Given the burgeoning interest in the PARP superfamily enzymes as drug targets and their role as mediators of cellular signaling processes, identifying and characterizing the targets of these enzymes is critical.…”

Section: Introductionmentioning

confidence: 99%

Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets

et al. 2018

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Poly (ADP-ribose)ylation is a dynamic protein modification that regulates multiple cellular processes. Here, we describe a system for identifying and characterizing PARylation events that exploits the ability of a PBZ (PAR-binding zinc finger) protein domain to bind PAR with high-affinity. By linking PBZ domains to bimolecular fluorescent complementation biosensors, we developed fluorescent PAR biosensors that allow the detection of temporal and spatial PARylation events in live cells. Exploiting transposon-mediated recombination, we integrate the PAR biosensor en masse into thousands of protein coding genes in living cells. Using these PAR-biosensor “tagged” cells in a genetic screen we carry out a large-scale identification of PARylation targets. This identifies CTIF (CBP80/CBP20-dependent translation initiation factor) as a novel PARylation target of the tankyrase enzymes in the centrosomal region of cells, which plays a role in the distribution of the centrosomal satellites.

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Section: Introductionmentioning

confidence: 99%

Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets

et al. 2018

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“…Although the IC 50 for PARP1/2 was not determined for compound 9 (Elliott et al, ), other compounds in the same series displayed IC 50 values for PARP1/2 of at least one order of magnitude above those for TNKS (Elliott et al, ; Paine et al, ).…”

Section: A Potential Role Of Tankyrase In the Formation Of β‐Catenin mentioning

confidence: 99%

“…The first potent toolbox TNKSi, XAV939 (Huang et al, ), IWR‐1 and IWR‐2 (Chen et al, ; Gunaydin et al, ), were discovered in phenotypic screens designed to identify antagonists of the Wnt/β‐catenin pathway, as were the inhibitors JW74 (Waaler et al, ), JW55 (Waaler et al, ), WIKI4 (James et al, ) and K‐756 (Okada‐Iwasaki et al, ). Numerous additional inhibitors were established through diverse approaches (see Zhan et al, ), including screening for compounds that rescue tankyrase‐induced lethality of yeast cells (Yashiroda et al, ) or induce a mitotic spindle defect (Johannes et al, ), fragment screening (Larsson et al, ; de Vicente et al, ), proteomics (Thomson et al, ), in silico screening or substructure searching, followed by compound optimization (Bregman et al, ; Elliott et al, ), screening of a DNA‐encoded library (Samain et al, ) and extensive structure–activity relationship studies, assisted by the structural analysis of tankyrase/PARP:inhibitor complexes (Hua et al, ; Shultz et al, ; Voronkov et al, ; Narwal et al, ; Liscio et al, ; Qiu et al, ; Haikarainen et al, ; Kumpan et al, ; Nkizinkiko et al, ; Paine et al, ; Haikarainen et al, ; Thomson et al, ). Numerous more drug‐like molecules, with optimized pharmacological properties, are now available, for example, G007‐LK (Lau et al, ; Voronkov et al, ) and NVP‐TNKS656 (Shultz et al, ).…”

Section: Tankyrase Inhibitorsmentioning

confidence: 99%

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

Mariotti

Pollock

Guettler

2017

British J Pharmacology

112

120

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The Wnt/β‐catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration‐limited pathway components and a wide range of post‐translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP‐ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β‐catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the β‐catenin destruction complex, and targets it for degradation, thereby fine‐tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt‐dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/β‐catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re‐tune Wnt/β‐catenin signalling in colorectal cancer cells.Linked ArticlesThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

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“…The Wnt/b-catenin pathway is dysregulated in the vast majority of colorectal cancers 34 . Inhibiting tankyrase has been explored as a strategy to re-tune oncogenically dysregulated Wnt/b-catenin signaling in cancers with mutations in the tumor suppressor and destruction complex component APC (adenomatous polyposis coli) 10,[35][36][37][38][39][40] . Whilst tankyrase inhibitors can suppress tumor cell growth, in-vivo studies have also pointed to different degrees of tankyrase-inhibitor-induced intestinal toxicity in mice 35,39,41 .…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, tankyrase inhibition typically leads not only to the accumulation of many of its substrates but also of tankyrase itself 6,7,35,37,40 . Moreover, catalysis-independent functions of tankyrase are emerging, and these may be accentuated when tankyrase and its substrates accumulate upon tankyrase catalytic inhibition.…”

Section: Introductionmentioning

confidence: 99%

Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase

Pollock

Liu

Zaleska

et al. 2019

Preprint

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The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/bcatenin signaling and telomere maintenance. The ARCs recognise a conserved tankyrasebinding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase's poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent "scaffolding" mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR). We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.

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Design and discovery of 3-aryl-5-substituted-isoquinolin-1-ones as potent tankyrase inhibitors

Cited by 11 publications

References 17 publications

Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets

Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase

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