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PARP modulators and treatment of cancer

一种PARP-1、芳香化合物的技术，应用在PARP调节剂和癌症的治疗领域，能够解决体内效果限制等问题

Inactive Publication Date: 2008-07-30
BIPAR SCI INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the approach using benzamide analogues has limited in vivo effects

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  • PARP modulators and treatment of cancer
  • PARP modulators and treatment of cancer
  • PARP modulators and treatment of cancer

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[0116] Examples of inflammation include, but are not limited to, systemic inflammation and local conditions related to the migration and attraction of monocytes, leukocytes and / or neutrophils. Inflammation can result from infection with pathogenic organisms (including gram-positive bacteria, gram-negative bacteria, viruses, fungi, and parasites such as protozoa and helminths), transplant rejection (including solid organs such as kidney, liver, heart, lung Or corneal rejection, and bone marrow transplant rejection, including graft-versus-host disease (GVHD)), or local chronic or acute autoimmune or allergic reactions. Autoimmune diseases include acute glomerulonephritis; rheumatoid or reactive arthritis; chronic glomerulonephritis; inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, and necrotizing enterocolitis; Note related syndromes; inflammatory skin diseases such as contact dermatitis, atopic dermatitis, psoriasis; systemic lupus erythematosus (SLE), a...

Embodiment 1

[0170] Enzyme activity of wild-type arginine-34 and arginine-138 mutant PARP-1

[0171] Assays were performed three times as described (Kun et al. (2004) Biochemistry, 43:210-216) (200 μM 3H-labeled NAD+, 28 dpm / pmol, 0.5 pmol PARP-1, 3 mM spermine, pH 7.3 t=7.5 min ). The same results were obtained when ATP was replaced by its non-hydrolyzable analog (Kun et al. (2004) Biochemistry, 43:210-216).

[0172] Zn in PARP-1 2+The effect of substituting glycine for arginine-34 in finger 1 is shown in Figure 1. The overall enzymatic activity of PARP-1 is not affected by this mutation, whereas the inhibitory effect of ATP (or its non-hydrolyzable analogs) is abolished. These results indicate that only PARP-1 is sensitive to the regulation of ATP. Zn 2+ The mutation of arginine-138 to isoleucine in finger 2 had a negligible effect on the inhibition of ATP, confirming our view that, Zn 2+ Arginine-34 of finger 1 is the interaction site of ATP and PARP-1.

Embodiment 2

[0174] Effect of ATP on PARP-1 Activity in Jurkat Nuclei

[0175] Equivalent to 2×10 5 Nuclei of Jurkat cells were pre-incubated in the presence of various concentrations of ATP. PARP activity was then measured by mixing with biotinylated-NAD (5 μM final concentration) and incubating for 10 minutes. After separation of proteins on an 8% SDS-PAGE gel, nitrocellulose-blotted, labeled proteins were detected by incubation with streptavidin-HPO complex (1 μg / ml) and by fluorescence photography. The results of three replicates are expressed in optical density units.

[0176] The effect of externally added ATP (or its non-hydrolyzable analogs) on PARP-1 activity in isolated Jurkat nuclei is shown in FIG. 2 . A drastic inhibition of PARP-1 activity is evident, and inhibition in the nucleus can be even greater than that reported for separase, since ATP has a Ki between 2 and 2.5 mM for the pure enzyme (3), whereas in the nucleus 1 mM ATP already inhibited 80% of PARP-1. This di...

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Abstract

The invention relates to a method of modulating poly (ADP-ribose) polymerase-l (PARP-I) activity in a mammal comprising administering to a mammal an effective amount of an organic aromatic compound having from 4 to about 35 carbon atoms, wherein the organic aromatic compound is capable of binding the arginine-34 moiety located in Zinc finger-1 of the PARP-I enzyme and wherein the organic aromatic compound has electron donating capabilities such that it's tr-electron system will interact with the positively charged (cationic) guanidinium moiety of the specific arginine-34 residue of the Zinc-1 finger of PARP-I and does not contain benzamide or lactam substituents. In particular, substituted benzopyrones and substituted indoles and their pharmaceutical compositions containing such compounds that modulate the activity of PARP-I, are described. The invention is also directed to the composition of matter, kits and methods for their therapeutic and / or prophylactic use in treating diseases and disorders described herein, by administering effective amounts of such compounds. Preferably, the compositions and methods provided herein inhibit PARP activity.

Description

[0001] cross reference [0002] This application claims priority to US Provisional Application No. 60 / 689,178, filed June 10, 2005, the entire contents of which are incorporated herein by reference. [0003] Statement Regarding Federally Sponsored Research [0004] This invention was made in part with US Government support through NIH grants HL 59693 and HL 35561. Background of the invention [0005] PARP (poly-ADP ribose polymerase) is involved in a variety of DNA-related functions, including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair, and also affects telomere length and chromosome stability ( d'Adda di Fagagna et al., 1999, Nature Gen. 23(1):76-80). Oxidative stress-induced hyperactivation of PARP depletes NAD+ and thus ATP, ultimately leading to cellular dysfunction or necrosis. This cellular suicide mechanism is involved in stroke, myocardial ischemia, diabetes, diabetes-related cardiovascular dysfunction, shock, traumati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/00C12P13/00
CPCA61K31/366C07D209/16C07D209/08A61K31/404C07D311/10A61P17/02A61P19/02A61P19/10A61P21/00A61P21/04A61P25/00A61P25/02A61P25/14A61P25/16A61P25/18A61P25/28A61P25/30A61P27/02A61P29/00A61P3/00A61P31/12A61P31/18A61P35/00A61P37/00A61P37/06A61P37/08A61P39/06A61P43/00A61P9/00A61P9/10A61P3/10Y02A50/30
Inventor E·库恩J·门德莱耶夫P·鲍尔
Owner BIPAR SCI INC
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