Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2

Moustakim, Moses; Riedel, Kerstin; Schuller, M.; Gehring, André P.; Monteiro, Octovia; Martin, Sarah P.; Fedorov, Oleg; Heer, Jag; Dixon, Darren J.; Elkins, J.M.; Knapp, S.; Bracher, Franz; Brennan, P.E.

doi:10.1016/j.bmc.2018.03.020

Cited by 28 publications

(22 citation statements)

References 41 publications

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“…The clinical success of PARP inhibitors in BRCA1/2-mutated breast and ovarian cancers has ignited a push for more widespread use of these compounds in cancers with a molecular signature of defective HR, irrespec-ADP-ribose mechanisms and disease 7 tive of which HR gene is mutated and in which tissue the tumour originated (Pilie et al, 2019). Similarly, novel inhibitors that selectively target different PARPs, including PARP3, PARP5a/5b, PARP7, PARP10, PARP11 and PARP14 are under investigation for the targeted treatment of cancers with alterations in particular pathways (Ishida et al, 2006;Lindgren et al, 2013;Iwata et al, 2016;Wang, Y. Q. et al, 2016b;Ferri et al, 2017;Yoneyama-Hirozane et al, 2017;Kirby et al, 2018;Moustakim et al, 2018;Murthy et al, 2018).…”

Section: Parp1 and Cell Deathmentioning

confidence: 99%

ADP-ribosylation: from molecular mechanisms to human disease

Hoch

Polo

2020

Genet. Mol. Biol.

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Post-translational modification of proteins by ADP-ribosylation, catalysed by poly (ADP-ribose) polymerases (PARPs) using NAD + as a substrate, plays central roles in DNA damage signalling and repair, modulates a range of cellular signalling cascades and initiates programmed cell death by parthanatos. Here, we present mechanistic aspects of ADP-ribose modification, PARP activation and the cellular functions of ADP-ribose signalling, and discuss how this knowledge is uncovering therapeutic avenues for the treatment of increasingly prevalent human diseases such as cancer, ischaemic damage and neurodegeneration.The PARP1 active site is formed between the catalytic domain (ART domain) and the helical domain (HD) Figure 1 -Schematic mechanism of ADP ribosylation reaction and the catalytic domain of DNA-dependant PARPs. A) A simplified overview of the (ADP)-ribosylation reactions catalysed by PARPs. The final products depend on the acceptor residue acting as a nucleophile (Nu, in blue). PARP1 active-site residues interacting with the ribose-nicotinamide moiety of NAD + are illustrated in orange. B) The NAD + (modelled based on the human PARP1 bound to benzamide adenine dinucleotide [PDB: 6BHV], carbon atoms in yellow) in an extended conformation, bound to the catalytic domain of human PARP1 (ART in cartoon, orange, [PDB: 6BHV]). The residues involved in the catalysis are presented as sticks. C) Superposed cartoon view of human PARP-1 ART domain (orange, [PDB: 6BHV]), PARP1 (light blue, [PDB: 5WS1]) and PARP2 (green, [PDB: 3KJD]) showing the structure of the entire catalytic domains (ART and HD). The modelled NAD + (in yellow) denotes the donor site, while a molecule of ADP (modelled by superimposing the structures of chicken PARP1 [PDB: 1A26] to the human PARP1 [PDB: 3KJD]) indicates the acceptor site. Donor loop (D-loop) and acceptor loop are labelled. D) Surface representation of human PARP1 [PDB: 3KJD] with NAD + modelled into the active site. The ribose group to be attacked is exposed to the solvent. ADP-ribose mechanisms and disease 3 ADP-ribose mechanisms and disease 13

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Section: Parp1 and Cell Deathmentioning

confidence: 99%

ADP-ribosylation: from molecular mechanisms to human disease

Hoch

Polo

2020

Genet. Mol. Biol.

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“…Among nineteen complex crystal structures, there are five endogenous ligands such as ADP and ADP-ribose: one structure for macro domain 1 (PDB ID, 3Q6Z), one structure for macro domain 2 (PDB ID, 3Q71), two structures for macro domain 1/2 (PDB ID, 3VFQ, 4D86) and one structure for macro domain 3 (PDB ID, 4ABK). The ligands of other fourteen structures are small molecular inhibitors: one structure for macro domain 2 (PDB ID, 5O2D) and thirteen structures for the catalytic domain (PDB ID, 3GOY, 3SE2, 3SMI, 3SMJ, 4F1L, 4F1Q, 4PY4, 5LXP, 5LYH, 5NQE, 5V7T, 5V7W, 6G0W) ( http://www.rcsb.org/ , 2019.01.31) (Andersson et al, 2012 ; Wahlberg et al, 2012 ; Forst et al, 2013 ; Peng et al, 2017 ; Schuller et al, 2017 ; Upton et al, 2017 ; Yoneyama-Hirozane et al, 2017 ; Holechek et al, 2018 ; Moustakim et al, 2018 ). All the PARP14 ligands released in the PDB are summarized in Table 1 .…”

Section: Inhibitors Of Parp14 Domainsmentioning

confidence: 99%

Research Progress on PARP14 as a Drug Target

Qin

Cao

et al. 2019

Front. Pharmacol.

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Poly-adenosine diphosphate-ribose polymerase (PARP) implements posttranslational mono- or poly-ADP-ribosylation modification of target proteins. Among the known 18 members in the enormous family of PARP enzymes, several investigations about PARP1, PARP2, and PARP5a/5b have been launched in the past few decades; more specifically, PARP14 is gradually emerging as a promising drug target. An intact PARP14 (also named ARTD8 or BAL2) is constructed by macro1, macro2, macro3, WWE, and the catalytic domain. PARP14 takes advantage of nicotinamide adenine dinucleotide (NAD+) as a metabolic substrate to conduct mono-ADP-ribosylation modification on target proteins, taking part in cellular responses and signaling pathways in the immune system. Therefore, PARP14 has been considered a fascinating target for treatment of tumors and allergic inflammation. More importantly, PARP14 could be a potential target for a chemosensitizer based on the theory of synthetic lethality and its unique role in homologous recombination DNA repair. This review first gives a brief introduction on several representative PARP members. Subsequently, current literatures are presented to reveal the molecular mechanisms of PARP14 as a novel drug target for cancers (e.g., diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, and hepatocellular carcinoma) and allergic inflammatory. Finally, potential PARP inhibitor-associated adverse effects are discussed. The review could be a meaningful reference for innovative drug or chemosensitizer discovery targeting to PARP14.

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“…N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69) was identified as a novel allosteric ARTD8 inhibitor [ 111 ]. Recently, a role for the ADP-ribosyltransferase 8 (ARTD8) has been identified in the dynamics of the DNA replication controlled by ATR [ 112 ], as it modulates the response to ATR-CHK1 pathway inhibitors.…”

Section: Mono(adp-ribosyl) Transferases (Mart)mentioning

confidence: 99%

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

Poltronieri

Celetti

Palazzo

2021

Cells

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Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.

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Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2

Abstract: Graphical abstract

Cited by 28 publications

References 41 publications

ADP-ribosylation: from molecular mechanisms to human disease

ADP-ribosylation: from molecular mechanisms to human disease

Research Progress on PARP14 as a Drug Target

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

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