Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15

Nizi, Maria Giulia; Maksimainen, Mirko M.; Murthy, Sudarshan; Massari, Serena; Alaviuhkola, Juho; Lippok, Barbara E.; Sowa, Sven T.; Galera‐Prat, Albert; Prunskaite‐Hyyryläinen, Renata; Lüscher, Bernhard; Korn, Patricia; Lehtiö, L.; Tabarrini, Oriana

doi:10.1016/j.ejmech.2022.114362

Cited by 6 publications

(24 citation statements)

References 40 publications

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“…The titration experiments with 21 and 27 revealed that they are indeed the most potent PARP10 inhibitors described so far also in cell assays (Figure 5B). Especially 27 was effective in rescuing the cells with an EC 50 of 150 nM (Table 4), 4-fold more potent than the compounds disclosed earlier, 35 and again the ranking is in good agreement with the potencies measured in enzymatic assays.…”

Section: Resultssupporting

confidence: 77%

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[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

Murthy

Nizi

Maksimainen

et al. 2022

Preprint

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Here we report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogs and their crystal structures with TNKS2, PARP2, PARP14 and PARP15. Based on the substitution pattern, we were able to identify The 3-amino derivatives 21 (OUL243) and 27 (OUL232), as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14 and PARP15 at nM potencies, with compound 27 being the most potent PARP10 inhibitor described to date with an IC50 of 7.8 nM and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity towards PARP2. The scaffold does not possess inherent cell toxicity and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of the TBT scaffold for future drug development efforts towards selective inhibitors against specific enzymes.

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Section: Resultssupporting

confidence: 77%

“…Notably, no inhibitors of PARP12 have been described earlier, and just a few PARP15 inhibitors have been discovered recently. 35,43…”

Section: Resultsmentioning

confidence: 99%

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

Murthy

Nizi

Maksimainen

et al. 2022

Preprint

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“… 95 (in the orange box), Tabarrini et al. 96 (in the blue box), and Lüscher et al 97 (in the pink box) along with the IC 50 .…”

Section: Mono-art Inhibitorsmentioning

confidence: 98%

“…On the basis of the good profile of benzyloxy derivative 8 , Tabarrini, Lehtiö et al in 2022 prepared a series of 15 p -methoxy benzamide analogues by mainly using cycloalkyls as a C-4 substituent. 96 With the aim to lock the amide through intramolecular hydrogen bonds and extend the compounds along the NAD + binding cleft, substituents of different sizes were also placed at the C-2 position. When tested against PARP10, most of the compounds showed inhibitory activity in the submicromolar range with the best compound represented by the cyclobutyl derivative 12 (IC 50 = 290 nM) followed by cyclopentyl derivative 13 (IC 50 = 593 nM) ( Figure 3 ).…”

Section: Mono-art Inhibitorsmentioning

confidence: 99%

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Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical “H–Y−Φ” motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.

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The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

Bai,

Yang,

Jia

et al. 2024

Medicinal Research Reviews

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Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long‐term medication‐induced drug resistance. Poly(ADP‐ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP‐DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first‐line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure–activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.

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Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15

Cited by 6 publications

References 40 publications

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

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