Discovery and characterization of novel potent PARP-1 inhibitors endowed with neuroprotective properties: From TIQ-A to HYDAMTIQ

Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in controlling cell survival or death. As a consequence, therapeutic interventions with PARP-1 inhibitors are sought in different pathological conditions such as cancer, cardiovascular and inflammatory diseases, as well as brain ischemia. In the first part of this work, as a continuation of our efforts in the field, we report the design, synthesis and biological appraisal of novel potent PARP-1 inhibitors. A crystallization experiment is carried out to ascertain the mode of binding to PARP-1 of the most potent compound, namely 2-((dimethylamino)methyl)-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one (HYDAMTIQ), whilst molecular modeling studies are performed to infer the role of water molecules in ligand binding. In the second part of the work, we discuss the results of HYDAMTIQ in models of brain ischemia as well as its preliminary physicochemical and pharmacokinetic characterization. Collectively, the data obtained qualify HYDAMTIQ as a novel lead candidate for advancement to clinical settings of brain ischemia.

[1]  P. Hergenrother,et al.  An enzymatic assay for poly(ADP-ribose) polymerase-1 (PARP-1) via the chemical quantitation of NAD(+): application to the high-throughput screening of small molecules as potential inhibitors. , 2004, Analytical biochemistry.

[2]  B. Durkacz,et al.  (ADP-ribose)n participates in DNA excision repair , 1980, Nature.

[3]  S. Snyder,et al.  Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  G. de Murcia,et al.  Poly(ADP-ribose) polymerase-1: what have we learned from the deficient mouse model? , 2000, Mutation research.

[5]  A. Boulares,et al.  Post‐allergen challenge inhibition of poly(ADP‐ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[6]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[7]  A. Tanaka,et al.  Synthesis of Furo[2,3-c]isoquinoline Derivatives† , 1978 .

[8]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2005, Nature.

[9]  E. Meli,et al.  Protection with metabotropic glutamate 1 receptor antagonists in models of ischemic neuronal death: time-course and mechanisms , 1999, Neuropharmacology.

[10]  G. Costantino,et al.  Towards new neuroprotective agents: design and synthesis of 4H-thieno[2,3-c] isoquinolin-5-one derivatives as potent PARP-1 inhibitors. , 2003, Farmaco.

[11]  Michael Gill,et al.  ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. , 1980, The Journal of biological chemistry.

[12]  P. Jeggo.  DNA repair: PARP – another guardian angel? , 1998, Current Biology.

[13]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[14]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[15]  Yasuhiro Suzuki,et al.  Poly(ADP-ribose) Polymerase-1 Inhibition Prevents Eosinophil Recruitment by Modulating Th2 Cytokines in a Murine Model of Allergic Airway Inflammation: A Potential Specific Effect on IL-51 , 2006, The Journal of Immunology.

[16]  G. Costantino,et al.  Novel Isoquinolinone-Derived Inhibitors of Poly(ADP-ribose) Polymerase-1: Pharmacological Characterization and Neuroprotective Effects in an in Vitro Model of Cerebral Ischemia , 2003, Journal of Pharmacology and Experimental Therapeutics.

[17]  D. Ferraris,et al.  Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic. , 2010, Journal of medicinal chemistry.

[18]  B. Berne,et al.  Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. , 2008, Journal of the American Chemical Society.

[19]  Mark Robson,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2010, The Lancet.

[20]  M. Jacobson,et al.  Poly(ADP-ribose) levels in carcinogen-treated cells , 1979, Nature.

[21]  G. Costantino,et al.  Docking studies on PARP-1 inhibitors: insights into the role of a binding pocket water molecule. , 2005, Bioorganic & medicinal chemistry.

[22]  F. Moroni.  Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. , 2008, Current opinion in pharmacology.

[23]  S. Snyder,et al.  Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia , 1997, Nature Medicine.

[24]  V. Schreiber,et al.  Poly(ADP-ribose): novel functions for an old molecule , 2006, Nature Reviews Molecular Cell Biology.

[25]  S. Kaufmann,et al.  PARP inhibition: PARP1 and beyond , 2010, Nature Reviews Cancer.

[26]  A. Boulares,et al.  Thieno[2,3-c]Isoquinolin-5-one, a Potent Poly(ADP-Ribose) Polymerase Inhibitor, Promotes Atherosclerotic Plaque Regression in High-Fat Diet-Fed Apolipoprotein E-Deficient Mice: Effects on Inflammatory Markers and Lipid Content , 2009, Journal of Pharmacology and Experimental Therapeutics.

[27]  Woody Sherman,et al.  High‐energy water sites determine peptide binding affinity and specificity of PDZ domains , 2009, Protein science : a publication of the Protein Society.

[28]  A. Chiarugi.  Poly(ADP-ribosyl)ation and stroke. , 2005, Pharmacological research.

[29]  A. Chiarugi,et al.  Post‐ischemic brain damage: targeting PARP‐1 within the ischemic neurovascular units as a realistic avenue to stroke treatment , 2009, The FEBS journal.

[30]  A. Chiarugi,et al.  Selective PARP‐2 inhibitors increase apoptosis in hippocampal slices but protect cortical cells in models of post‐ischaemic brain damage , 2009, British journal of pharmacology.

[31]  James R Kiefer,et al.  Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. , 2010, Journal of molecular biology.

[32]  R. Alvarez‐Gonzalez.  Genomic Maintenance: The p53 Poly(ADP-ribosyl)ation Connection , 2007, Science's STKE.