Over activation of poly (ADP-ribose) polymerase has been involved in the pathogenesis of several diseases including stroke, myocardial infarction, diabetes, shock, neurodegenerative disorder, allergy, and several other inflammatory processes.Owing to the dual response of PARP-1 to DNA damage and its involvement in cell death, pharmacol. modulation of PARP-1 activity may constitute a useful tool to increase the activity of DNA-binding antitumor drugs.Quant. structure activity relationship (QSAR) study vis-a-vis physico-chem. parameters and forward feed neural network anal. for a series of phthalazinone derivatives as potent inhibitors of poly (ADP-ribose) polymerase was performed.The result of QSAR studies obtained allows us to recognize such physico-chem. parameters of phthalazinone derivatives which can be strictly related to the PARP-1 inhibitory activity.

01 Dec 2009·International journal of radiation oncology, biology, physicsQ2 · MEDICINE

Poly(ADP-Ribose) Polymerase-1 and DNA-Dependent Protein Kinase Have Equivalent Roles in Double Strand Break Repair Following Ionizing Radiation

Q2 · MEDICINE

Article

Author: Jody Mitchell ; Graeme C.M. Smith ; Nicola J. Curtin

PURPOSE:

Radiation-induced DNA double strand breaks (DSBs) are predominantly repaired by nonhomologous end joining (NHEJ), involving DNA-dependent protein kinase (DNA-PK). Poly(ADP-ribose) polymerase-1 (PARP-1), well characterized for its role in single strand break repair, may also facilitate DSB repair. We investigated the activation of these enzymes by differing DNA ends and their interaction in the cellular response to ionizing radiation (IR).

METHODS AND MATERIALS:

The effect of PARP and DNA-PK inhibitors (KU-0058684 and NU7441) on repair of IR-induced DSBs was investigated in DNA-PK and PARP-1 proficient and deficient cells by measuring gammaH2AX foci and neutral comets. Complementary in vitro enzyme kinetics assays demonstrated the affinities of DNA-PK and PARP-1 for DSBs with varying DNA termini.

RESULTS:

DNA-PK and PARP-1 both promoted the fast phase of resolution of IR-induced DSBs in cells. Inactivation of both enzymes was not additive, suggesting that PARP-1 and DNA-PK cooperate within the same pathway to promote DSB repair. The affinities of the two enzymes for oligonucleotides with blunt, 3' GGG or 5' GGG overhanging termini were similar and overlapping (K(d)(app) = 2.6-6.4nM for DNA-PK; 1.7-4.5nM for PARP-1). DNA-PK showed a slightly greater affinity for overhanging DNA and was significantly more efficient when activated by a 5' GGG overhang. PARP-1 had a preference for blunt-ended DNA and required a separate factor for efficient stimulation by a 5' GGG overhang.

CONCLUSION:

DNA-PK and PARP-1 are both required in a pathway facilitating the fast phase of DNA DSB repair.

12 Feb 2009·Journal of medicinal chemistryQ1 · MEDICINE

Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly(ADP-Ribose) Polymerase-1 Inhibitors

Q1 · MEDICINE

Article

Author: Chen, Gang-Ying ; Fang, Wei ; Zhang, Li−Na ; Wu, Peng-Fei ; Jiang, Feng-Chao ; Zhang, Wen-Ting ; Wang, Yue ; Chen, Jian-Guo ; Gu, Jun ; Zhu, Yi-Jing ; Chen, Xiang-Long ; Cao, Bao-Shuai ; Ruan, Jin-Lan

A series of novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors were designed within 2-aminothiazole analogues (4-10) based on a constructed three-dimensional pharmacophore model. After synthesis, the inhibitory effect on PARP-1 activity and the cytoprotective action of these compounds were tested and evaluated. Among them, compounds 4-6 and 10 appeared to be potent PARP-1 inhibitors with IC(50) values less than 1 microM, which had been perfectly predicted by pharmacophore model. These compounds proved to be highly potent against cell injury induced by H(2)O(2) and oxygen-glucose deprivation (OGD) in PC12 cells. These novel 2-aminothiazole analogues are potentially applicable as neuroprotective agents for the treatment of neurological diseases.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United Kingdom	KuDOS Pharmaceuticals Ltd.	14 Apr 2005

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