4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10

Murthy, Sudarshan; Desantis, Jenny; Verheugd, Patricia; Maksimainen, Mirko M.; Venkannagari, Harikanth; Massari, Serena; Ashok, Yashwanth; Obaji, Ezeogo; Nkizinkinko, Yves; Lüscher, Bernhard; Tabarrini, Oriana; Lehtiö, L.

doi:10.1016/j.ejmech.2018.06.047

Cited by 27 publications

(48 citation statements)

References 33 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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“…Selectivity boosts towards mono-ARTs induced by hydrophobic moieties extending towards the acceptor site has also be seen previously with PARP10 inhibitor development. 18,34…”

Section: Discussionmentioning

confidence: 99%

“…1 belongs to nicotinamide mimicking inhibitors and partially resembles OUL35, a selective inhibitor of PARP10 17 . From the structure activity relationship study of PARP10 inhibitors 18 we identified an analog (2), which together with 1 formed a basis for our attempts to optimize the scaffold 1 in such a way that it would have selectivity towards different PARPs. A key feature of 2 is that it extends towards the acceptor site of the enzyme where protein to be modified is expected to bind.…”

Section: Introductionmentioning

confidence: 99%

Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs

Maksimainen

Murthy

Sowa

et al. 2021

Preprint

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The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.

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“…In the beginning years, the developed inhibitors were designed targeting a group of ART enzymes; in recent years, novel compounds have been developed specific for a single ART enzyme, with effects at nanomolar concentration. For instance, there are new inhibitors targeting just ARTD10 [120,[127][128][129][130], ARTD11 [122,[131][132][133][134][135][136][137][138][139][140][141][142][143][144]. or ARTD14/PARP7 [142][143][144].…”

Section: Other Marylating Art Enzymes Linked To Cancer and Potential Enzyme Inhibitorsmentioning

confidence: 99%

“…MARylation of ARTD10 is recognized by ARTD8/PARP14, that is docked to the MAR structure to form a protein complex. Several molecules have shown the potential to selectively inhibit ARTD10 [127][128][129][130]14], such as the cell-permeable OU135, a 3,4-dihydroisoquinolin-1(2H)-one that contains a methyl group at the C-5 position and a substituted pyridine at the C-6 position [128], and 4-benzyloxybenzimide derivatives [127]. The targets of ARTD10 that could require a fine tuning of MARylation are glycogen synthase kinase GSK3β, NEMO/IKK-γ, a subunit of NF-kB transcription factor, histone H3 and the polo-like kinase PLK1 [1].…”

Section: Other Marylating Art Enzymes Linked To Cancer and Potential Enzyme Inhibitorsmentioning

confidence: 99%

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri¹,

Misawa²,

Masutani³

2021

Preprint

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Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10

Cited by 27 publications

References 33 publications

ADP-ribosylation: from molecular mechanisms to human disease

ADP-ribosylation: from molecular mechanisms to human disease

Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

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