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Jonathan M. Elkins - One of the best experts on this subject based on the ideXlab platform.
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Discovery of a novel allosteric inhibitor scaffold for Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) macrodomain 2
Bioorganic & medicinal chemistry, 2018Co-Authors: Moses Moustakim, Kerstin Riedel, M. Schuller, André P. Gehring, Octovia P. Monteiro, Sarah P. Martin, Oleg Fedorov, Jag Paul Heer, Darren J. Dixon, Jonathan M. ElkinsAbstract:The Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP Ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.
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Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14
ACS chemical biology, 2017Co-Authors: M. Schuller, Kerstin Riedel, André P. Gehring, Ian Gibbs-seymour, Kristin Uth, Christian Sieg, Ivan Ahel, Franz Bracher, Benedikt M. Kessler, Jonathan M. ElkinsAbstract:Macrodomains are conserved protein interaction modules that can be found in all domains of life as well as in certain viruses. Macrodomains mediate recognition of sequence motifs harbouring adenosine Diphosphate Ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterisation of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallisation of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prev...
M. Schuller - One of the best experts on this subject based on the ideXlab platform.
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Discovery of a novel allosteric inhibitor scaffold for Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) macrodomain 2
Bioorganic & medicinal chemistry, 2018Co-Authors: Moses Moustakim, Kerstin Riedel, M. Schuller, André P. Gehring, Octovia P. Monteiro, Sarah P. Martin, Oleg Fedorov, Jag Paul Heer, Darren J. Dixon, Jonathan M. ElkinsAbstract:The Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP Ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.
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Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14
ACS chemical biology, 2017Co-Authors: M. Schuller, Kerstin Riedel, André P. Gehring, Ian Gibbs-seymour, Kristin Uth, Christian Sieg, Ivan Ahel, Franz Bracher, Benedikt M. Kessler, Jonathan M. ElkinsAbstract:Macrodomains are conserved protein interaction modules that can be found in all domains of life as well as in certain viruses. Macrodomains mediate recognition of sequence motifs harbouring adenosine Diphosphate Ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterisation of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallisation of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prev...
Frank Mayer - One of the best experts on this subject based on the ideXlab platform.
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Poly (ADP-Ribose) Polymerase-1 (PARP1) Deficiency and Pharmacological Inhibition by Pirenzepine Protects From Cisplatin-Induced Ototoxicity Without Affecting Antitumor Efficacy
Frontiers in cellular neuroscience, 2019Co-Authors: Anke Tropitzsch, Marcus Müller, François Paquet-durand, Frank Mayer, Hans-georg Kopp, Andre Schrattenholz, Andrea Müller, Hubert LöwenheimAbstract:Cisplatin remains an indispensable drug for the systemic treatment of many solid tumors. However, a major dose-limiting side-effect is ototoxicity. In some scenarios, such as treatment of germ cell tumors or adjuvant therapy of non-small cell lung cancer, cisplatin cannot be replaced without undue loss of efficacy. Inhibition of Polyadenosine Diphosphate-Ribose polymerase-1 (PARP1), is presently being evaluated as a novel anti-neoplastic principle. Of note, cisplatin-induced PARP1 activation has been related to inner ear cell death. Thus, PARP1 inhibition may exert a protective effect on the inner ear without compromising the antitumor activity of cisplatin. Here, we evaluated PARP1 deficiency and PARP1 pharmacological inhibition as a means to protect the auditory hair cells from cisplatin-mediated ototoxicity. We demonstrate that cisplatin-induced loss of sensory hair cells in the organ of Corti is attenuated in PARP1-deficient cochleae. The PARP inhibitor pirenzepine and its metabolite LS-75 mimicked the protective effect observed in PARP1-deficient cochleae. Moreover, the cytotoxic potential of cisplatin was unchanged by PARP inhibition in two different cancer cell lines. Taken together, the results from our study suggest that the negative side-effects of cisplatin anti-cancer treatment could be alleviated by a PARP inhibition adjunctive therapy.
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Polyadenosine Diphosphate-Ribose polymerase (PARP) inhibition as a means of protecting the inner ear from cisplatin (CDDP)-mediated ototoxicity without affecting antitumor efficacy in vitro.
Journal of Clinical Oncology, 2010Co-Authors: Frank Mayer, Hans-georg Kopp, Martin R Mueller, Elke Malenke, A. Schrattenholz, H. LoewenheimAbstract:e13501 Background: Hearing loss can be the dose limiting toxicity of CDDP. In the treatment of germ cell tumors (GCT) or adjuvant therapy of non-small cell lung cancer (NSCLC), CDDP cannot be replaced without loss of efficacy. Inhibition of PARP, an enzyme of the base excision repair pathway, is a novel anti-neoplastic principle. PARP-activation has been identified to induce cell death following inner ear trauma. We evaluated PARP-inhibition by pirenzepin as a means to protect the ear from CDDP. Methods: In an in vitro culture model, inner ears were treated continuously with 1.4 μM CDDP. Ears were obtained from heterozygous and homozygous PARP-knock out mice and wild-type controls at postnatal day 7. The number of preserved hair cell stereocilia bundles was counted by fluorescence microscopy after labeling with phalloidin. Cytotoxicity of CDDP and the effect of pirenzepin were assessed by MTS-assays and flow cytometry using the cell lines 2102EP, NT2 (both GCT) and NCI-H460 (NSCLC). Results: In wild-type ...
Kerstin Riedel - One of the best experts on this subject based on the ideXlab platform.
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Discovery of a novel allosteric inhibitor scaffold for Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) macrodomain 2
Bioorganic & medicinal chemistry, 2018Co-Authors: Moses Moustakim, Kerstin Riedel, M. Schuller, André P. Gehring, Octovia P. Monteiro, Sarah P. Martin, Oleg Fedorov, Jag Paul Heer, Darren J. Dixon, Jonathan M. ElkinsAbstract:The Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP Ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.
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Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14
ACS chemical biology, 2017Co-Authors: M. Schuller, Kerstin Riedel, André P. Gehring, Ian Gibbs-seymour, Kristin Uth, Christian Sieg, Ivan Ahel, Franz Bracher, Benedikt M. Kessler, Jonathan M. ElkinsAbstract:Macrodomains are conserved protein interaction modules that can be found in all domains of life as well as in certain viruses. Macrodomains mediate recognition of sequence motifs harbouring adenosine Diphosphate Ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterisation of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallisation of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prev...
André P. Gehring - One of the best experts on this subject based on the ideXlab platform.
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Discovery of a novel allosteric inhibitor scaffold for Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) macrodomain 2
Bioorganic & medicinal chemistry, 2018Co-Authors: Moses Moustakim, Kerstin Riedel, M. Schuller, André P. Gehring, Octovia P. Monteiro, Sarah P. Martin, Oleg Fedorov, Jag Paul Heer, Darren J. Dixon, Jonathan M. ElkinsAbstract:The Polyadenosine-Diphosphate-Ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP Ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.
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Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14
ACS chemical biology, 2017Co-Authors: M. Schuller, Kerstin Riedel, André P. Gehring, Ian Gibbs-seymour, Kristin Uth, Christian Sieg, Ivan Ahel, Franz Bracher, Benedikt M. Kessler, Jonathan M. ElkinsAbstract:Macrodomains are conserved protein interaction modules that can be found in all domains of life as well as in certain viruses. Macrodomains mediate recognition of sequence motifs harbouring adenosine Diphosphate Ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterisation of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallisation of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prev...