Small Molecule Microarray Based Discovery of PARP14 Inhibitors

Peng, Bo; Thorsell, A.G.; Karlberg, T.; Schüler, H.; Yao, Shao Q.

doi:10.1002/ange.201609655

Cited by 7 publications

(5 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are limited reports of cell-active monoPARP inhibitors, and of those published, potencies and intra-PARP family selectivity are modest. 3–10 Approved drugs that target PARP1 and PARP2 (niraparib and talazoparib) or PARP1, PARP2, and PARP3 (olaparib and rucaparib) are now in use for the treatment of a variety of cancers, and potent and selective inhibitors of PARP5a and PARP5b (tankyrases 1 and 2) have been reported to have antiproliferative activity in cancer cell lines and in vivo models. 11 MonoPARPs have been reported to have important roles in immunology, inflammation, and cancer; 12–14 however, these studies have relied almost exclusively on genetic perturbation techniques that often do not distinguish loss of catalytic activity from loss of the entire protein.…”

Section: Introductionmentioning

confidence: 99%

“…There have been limited reports describing inhibitor screening using enzyme assays, and in many cases high concentrations of enzyme have been required to generate sufficient signal to background to make the assays robust. 8,16–19 Also, previous reports have used thermal shift assays (TSAs), 20 surface plasmon resonance (SPR), 20 DNA-encoded libraries (DELs) 21 and small-molecule microarrays (SMMs) 7 to identify and characterize monoPARP ligands; however, these techniques are either not quantitative (i.e., TSAs) or low-throughput (i.e., SPR), or require the development of expertise in complex chemistry (i.e., DELs and SMMs). Additionally, there has been a report of an AlphaScreen assay to identify inhibitors of the ADP-ribose binding macrodomains of PARP9, PARP14, and PARP15; however, this strategy was not shown to identify inhibitors of the catalytic activity of these proteins.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes

et al. 2020

View full text Add to dashboard Cite

Mono(ADP-ribosylation) (MARylation) and poly(ADP-ribosylation) (PARylation) are posttranslational modifications found on multiple amino acids. There are 12 enzymatically active mono(ADP-ribose) polymerase (monoPARP) enzymes and 4 enzymatically active poly(ADP-ribose) polymerase (polyPARP) enzymes that use nicotinamide adenine dinucleotide (NAD+) as the ADP-ribose donating substrate to generate these modifications. While there are approved drugs and clinical trials ongoing for the enzymes that perform PARylation, MARylation is gaining recognition for its role in immune function, inflammation, and cancer. However, there is a lack of chemical probes to study the function of monoPARPs in cells and in vivo. An important first step to generating chemical probes for monoPARPs is to develop biochemical assays to enable hit finding, and determination of the potency and selectivity of inhibitors. Complicating the development of enzymatic assays is that it is poorly understood how monoPARPs engage their substrates. To overcome this, we have developed a family-wide approach to developing robust high-throughput monoPARP assays where the enzymes are immobilized and forced to self-modify using biotinylated-NAD+, which is detected using a dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) readout. Herein we describe the development of assays for 12 monoPARPs and 3 polyPARPs and apply them to understand the potency and selectivity of a focused library of inhibitors across this family.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Small molecule microarray screening is an efficient high-throughput method initially designed to examine the interaction between ligands and proteins [ 111 ]. This method is also known as two-dimensional combinatorial screening (2DCS), which simultaneously explores both RNA and ligands [ 112 ].…”

Section: Identification Of Small Molecules Interacting With Mirsmentioning

confidence: 99%

Targeting MicroRNAs with Small Molecules

Tadesse,

Benhamou

2024

ncRNA

View full text Add to dashboard Cite

MicroRNAs (miRs) have been implicated in numerous diseases, presenting an attractive target for the development of novel therapeutics. The various regulatory roles of miRs in cellular processes underscore the need for precise strategies. Recent advances in RNA research offer hope by enabling the identification of small molecules capable of selectively targeting specific disease-associated miRs. This understanding paves the way for developing small molecules that can modulate the activity of disease-associated miRs. Herein, we discuss the progress made in the field of drug discovery processes, transforming the landscape of miR-targeted therapeutics by small molecules. By leveraging various approaches, researchers can systematically identify compounds to modulate miR function, providing a more potent intervention either by inhibiting or degrading miRs. The implementation of these multidisciplinary approaches bears the potential to revolutionize treatments for diverse diseases, signifying a significant stride towards the targeting of miRs by precision medicine.

show abstract

“…However, this compound is limited in its ability to be classified as a selective PARP inhibitor, because its potency has not been assessed against all PARP enzymes. Another promising lead has been H10 , as proposed by Peng et al ., which was found to inhibit PARP14 activity at an IC 50 of 0.49 ± 0.07 μM in vitro [ 18 ]. H10 operates as a bidentate inhibitor, targeting both the conserved nicotinamide binding site and the less conserved adenine binding site within PARP14’s catalytic domain.…”

Section: Parp14 Inhibitorsmentioning

confidence: 99%

The Potential Association Between PARP14 and SARS-CoV-2 Infection (COVID-19)

2021

View full text Add to dashboard Cite

Understanding the potential association between the poly (ADP-ribose) polymerase member 14 (PARP14) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may aid in understanding the host immunopathological response to the virus. PARP14 has an emerging role in viral infections, and this article considers its potential mechanisms for action in either a pro- or anti-viral manner. It is evident that more experimental work is required; however, PARP14 appears vital in controlling the interferon response to the SARS-CoV-2 infection and has potential roles in balancing the proinflammatory cytokines of the cytokine storm. Furthermore, the SARS-CoV-2 macrodomain can prevent the PARP14-mediated antiviral response, suggesting a more complex relationship between PARP14 activity and SARS-CoV-2 infections.

show abstract

Small Molecule Microarray Based Discovery of PARP14 Inhibitors

Cited by 7 publications

References 31 publications

Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes

Forced Self-Modification Assays as a Strategy to Screen MonoPARP Enzymes

Targeting MicroRNAs with Small Molecules

The Potential Association Between PARP14 and SARS-CoV-2 Infection (COVID-19)

Contact Info

Product

Resources

About