On the Way to Selective PARP‐2 Inhibitors. Design, Synthesis, and Preliminary Evaluation of a Series of Isoquinolinone Derivatives

Pellicciari, Roberto; Camaioni, Emidio; Costantino, Gabriele; Formentini, Laura; Sabbatini, Paola; Venturoni, Francesco; Eren, Gökçen; Bellocchi, Daniele; Chiarugi, Alberto; Moroni, Flavio

doi:10.1002/cmdc.200800010

Cited by 58 publications

(57 citation statements)

References 25 publications

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“…Of note, we show that tissue PAR content is reduced in KO mice upon PJ34 administration, which is in keeping with the notion that PARP-1 contributes to the majority of PAR formations [13,14]. However, given that the drug is not strictly PARP-1 selective [36], we cannot rule out the possibility that inhibition of additional PARPs, including PARP-2 [37], may have contributed to the pharmacodynamic effects of PJ34.…”

Section: Discussionsupporting

confidence: 61%

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

et al. 2014

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Mitochondrial disorders are deadly childhood diseases for which therapeutic remedies are an unmet need. Given that genetic suppression of the nuclear enzyme poly (adenine diphosphate-ribose) polymerase(PARP)-1 improves mitochondrial functioning, we investigated whether pharmacological inhibition of the enzyme affords protection in a mouse model of a mitochondrial disorder. We used mice lacking the Ndufs4 subunit of the respiratory complex I (Ndufs4 knockout [ KO] mice); these mice undergo progressive encephalopathy and die around postnatal day 50. Mice were treated daily with the potent PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,Ndimethylamino)acetamide hydrochloride (PJ34); neurological parameters, PARP activity, and mitochondrial homeostasis were evaluated. We found that mice receiving N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride from postnatal day 30 to postnatal day 50 show reduced neurological impairment, and increased exploratory activity and motor skills compared with vehicle-treated animals. However, drug treatment did not delay or reduce death. We found no evidence of increased PARP activity within the brain of KO mice compared with heterozygous, healthy controls. Conversely, a 10-day treatment with the PARP inhibitor significantly reduced basal poly(ADP-ribosyl)ation in different organs of the KO mice, including brain, skeletal muscle, liver, pancreas, and spleen. In keeping with the epigenetic role of PARP-1, its inhibition correlated with increased expression of mitochondrial respiratory complex subunits and organelle number. Remarkably, pharmacological targeting of PARP reduced astrogliosis in olfactory bulb and motor cortex, but did not affect neuronal loss of KO mice. In light of the advanced clinical development of PARP inhibitors, these data emphasize their relevance to treatment of mitochondrial respiratory defects.

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Section: Discussionsupporting

confidence: 61%

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

et al. 2014

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“…2 Detailed knowledge is available about the transporter proteins at the membranes of hepatocytes and enterocytes involved in vectorial bile acid movement under both normal physiological and pathological conditions. 3,4,5 In contrast, the process of intracellular transfer of bile acids between the basolateral and the apical membrane is largely unexplored.…”

Section: Introductionmentioning

confidence: 92%

NMR Studies Reveal the Role of Biomembranes in Modulating Ligand Binding and Release by Intracellular Bile Acid Binding Proteins

Pedò¹,

Löhr²,

D’Onofrio³

et al. 2009

Journal of Molecular Biology

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“…A library of isoquinolinone derivatives was reported to display selectivity for PARP-2 up to 60-fold (44). This discrimination is thought to be due to a single residue variation of Glu763 in PARP-1 to Gln319 in PARP-2.…”

Section: Development Of Selective Parp Inhibitorsmentioning

confidence: 99%

Structural Implications for Selective Targeting of PARPs

et al. 2013

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Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that use NAD+ as a substrate to synthesize polymers of ADP-ribose (PAR) as post-translational modifications of proteins. PARPs have important cellular roles that include preserving genomic integrity, telomere maintenance, transcriptional regulation, and cell fate determination. The diverse biological roles of PARPs have made them attractive therapeutic targets, which have fueled the pursuit of small molecule PARP inhibitors. The design of PARP inhibitors has matured over the past several years resulting in several lead candidates in clinical trials. PARP inhibitors are mainly used in clinical trials to treat cancer, particularly as sensitizing agents in combination with traditional chemotherapy to reduce side effects. An exciting aspect of PARP inhibitors is that they are also used to selectivity kill tumors with deficiencies in DNA repair proteins (e.g., BRCA1/2) through an approach termed “synthetic lethality.” In the midst of the tremendous efforts that have brought PARP inhibitors to the forefront of modern chemotherapy, most clinically used PARP inhibitors bind to conserved regions that permits cross-selectivity with other PARPs containing homologous catalytic domains. Thus, the differences between therapeutic effects and adverse effects stemming from pan-PARP inhibition compared to selective inhibition are not well understood. In this review, we discuss current literature that has found ways to gain selectivity for one PARP over another. We furthermore provide insights into targeting other domains that make up PARPs, and how new classes of drugs that target these domains could provide a high degree of selectivity by affecting specific cellular functions. A clear understanding of the inhibition profiles of PARP inhibitors will not only enhance our understanding of the biology of individual PARPs, but may provide improved therapeutic options for patients.

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On the Way to Selective PARP‐2 Inhibitors. Design, Synthesis, and Preliminary Evaluation of a Series of Isoquinolinone Derivatives

Cited by 58 publications

References 25 publications

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

NMR Studies Reveal the Role of Biomembranes in Modulating Ligand Binding and Release by Intracellular Bile Acid Binding Proteins

Structural Implications for Selective Targeting of PARPs

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