Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update

Jain, Priyancy G.; Patel, Bhumika

doi:10.1016/j.ejmech.2019.01.024

Cited by 114 publications

(68 citation statements)

References 101 publications

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“…Whereas the NAD + -dependent route of PARP-1 activation has been exhaustively exploited for designing new inhibitors, in the attempt of finding less cytotoxic inhibitors, more selective toward PARP-1, non-NAD + PARP-1 inhibitors, which work by different mechanisms of action of NAD + analogous, started to be developed and are currently under active experimentation [133,134].…”

Section: Therapeutic Implications Of Parp Inhibitorsmentioning

confidence: 99%

“…The inhibition of PARP-1 is being exploited for the treatment of various cancers, which include DNA repair-deficient ovarian, breast, and prostate cancers. PARPi clinical trials are now expanding to include various solid tumors such as pancreatic, biliary, urothelial, NSCLC, liver, colorectal, oesophageal, gastric, uterine, carcinosarcoma, brain metastasis Ewing's sarcoma, and others [134] (www.clinicaltrial.gov). The majority of these trials are monotherapy studies in patients with tumors harboring DNA repair defects while the remaining trials are combinations with chemotherapies, including platinums, taxanes, ATM (ataxia telangiectasia, mutated) inhibitors, ATR (ATM and RAD3-related) inhibitors, Wee1 inhibitors, and PI3K inhibitors, as well as with immune-oncology therapies.…”

Section: Therapy Of Cancermentioning

confidence: 99%

“…To obtain greater selectivity for PARP-1, novel next generation specific PARP-1i are being developed that target activation mechanisms unique to PARP-1 enzyme. This consist in either developing more specific NAD + such as PARPis by exclusively targeting amino acids of the adenosine-binding site of PARP-1 along with residues of nicotinamide binding site, as well as non-NAD + PARP-1is which work by different mechanisms of action of NAD + analogous [134].…”

Section: Therapy Of Cancermentioning

confidence: 99%

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Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Pazzaglia

Pioli

2019

Cells

158

135

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PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases.

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Section: Therapeutic Implications Of Parp Inhibitorsmentioning

confidence: 99%

Section: Therapy Of Cancermentioning

confidence: 99%

Section: Therapy Of Cancermentioning

confidence: 99%

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Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Pazzaglia

Pioli

2019

Cells

158

135

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“…Furthermore, the heteroaromatic ring improves the ability of binding to the enzyme [. 30,31]. Therefore, pyridine ring was chosen as the starting material and urea and carbohydrazide functional groups.…”

Section: Biological Evaluationmentioning

confidence: 99%

Design, synthesis, biological evaluation and molecular docking of novel moleculesto PARP-1 enzyme

Tok¹,

Kaymakçıoğlu²,

İlhan³

et al. 2019

Turk J Chem

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Poly (ADP-ribose) polymerase (PARP) enzyme catalyzes the transfer of ADP-ribose into target proteins.Therefore, PARP is responsible for DNA repair, cell proliferation, and cell death. In this study, potential PARP enzyme inhibitors were designed and synthesized. The synthesized compounds were elucidated by Fourier-transform infrared spectroscopy, 1 H NMR, 13 C NMR, heteronuclear single-quantum correlation, and mass spectrometry, and their purity was checked via thin-layer chromatography, high-performance liquid chromatography, and elemental analysis. A total of 63 newly synthesized compounds were screened in terms of PARP inhibition by cellular PARylation assay in the HeLa cell line. It was found that 19 compounds significantly inhibited the H 2 O 2 -induced cellular PARylation. The chemosensitizer effect of these compounds in cancer cells treated with doxorubicin (doxo) was investigated. It was found that the combination of potent PARP inhibitors with doxo potentiated a cytotoxic effect, similar to that of olaparib. The results of the molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis revealed that compound 60 might be classified as a potential PARP inhibitor candidate. Taken together, all of the results suggested that carbohydrazide derivatives could be a promising lead for the treatment for cancer disorders.

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mentioning

confidence: 99%

The investigation of Poly(ADP-ribose)polymerase activity in the context of nucleosome

2019

The Eleventh International Young Scientists School

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Poly(AdP-ribose)polymerase 1 (PARP1) -is a key enzyme that regulates the activity of dNA-repair machine. It makes PARP1 inhibitors promising anticancer drugs [1]. But some problems occur during therapy by these agents, for example cancer resistance or recurrence of disease. these problems require not only novel inhibitor developing, but also fundamental studies of PARP1 and its interaction with other proteins. to address this need we have developed a test-system, which allows analyzing PARP 1 activity in real time [2]. In this work we modified this test-system to observe PARP 1 activity on nucleosomes in vitro. Nucleosome is a dNA-protein complex that consist 147 bp dNA is wrapped around histone octamer. this model close to in vivo conditions more than the short model dNA, used previously. We showed the ability of our method shed light on PARP1 interaction with nucleosome, nucleosome with dNA-lesion and different proteins on nucleosome. PARP1 dNA-binding capacity after poly(AdP-ribose)lation and degradation of PAR by several enzymes (for example PARG) was studied. It is shown that automodified PARP1 can effectively bind DNA and DNA in nucleosome context after degradation of PAR. However, PARylation activity of this enzyme is dramatically decreased after modification and modification removing. In addition, an interaction of PARP1 with several nuclei proteins on nucleosome was studied. Some of these proteins can modulate PARP1 activity and cause decreasing of PARP1 inhibitors efficacy. Results of these studies show that the expression level of these proteins in patients can influence the choice of anticancer therapy strategy. Acknowledgements: the work was supported by the grant from RSf 17-74-20075. References 1. Jain P.G., Patel B.d. medicinal chemistry approaches of poly AdP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents. European Journal Med. Chemistry. 2019;1(165):198-215. 2. Kurgina T.A., Anarbaev R.O., Sukhanova M.V., Lavrik O.I. A rapid fluorescent method for the real-time measurement of poly(AdP-ribose) polymerase 1 activity. Analytical Biochemistry. 2018;15(545):91-97.

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Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update

Cited by 114 publications

References 101 publications

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Design, synthesis, biological evaluation and molecular docking of novel moleculesto PARP-1 enzyme

The investigation of Poly(ADP-ribose)polymerase activity in the context of nucleosome

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