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Application of GW3965 as PARP1 inhibitor

An inhibitor, trifluoromethyl technology, applied in the field of medicine

Active Publication Date: 2016-01-13
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing studies believe that elevated cholesterol is clearly related to the incidence of tumors, but there is no evidence for cholesterol-related drugs in this regard

Method used

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  • Application of GW3965 as PARP1 inhibitor
  • Application of GW3965 as PARP1 inhibitor
  • Application of GW3965 as PARP1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Detection by Cell-Free PARP1 Enzymatic Reaction System

[0028] A PARP1 activity detection kit is used to construct a cell-free PARP1 enzymatic reaction system, and the reaction system can activate the activity of PARP1 enzyme in an in vitro environment.

[0029] The PARP1 activity detection kit used in the examples was purchased from Trevigen, produced in the United States, with a model number of 4676-096-K.

[0030] PARP1 activity detection kit includes buffer, PARP1 recombinant protein, NAD + , single-strand break DNA, recombinant histone 1 (HistoneH1).

[0031] Configure the cell-free PARP1 enzymatic reaction system according to the PARP1 activity detection kit, the specific operation steps are as follows: add 50ng PARP1 recombinant protein (PARP1protein) to the buffer solution, the final concentration is 10mmol / LNAD + , The final concentration is 20mg / mL after single-strand break DNA. The final concentrations of the various components that make up the ...

Embodiment 2

[0038] Embodiment 2 utilizes in vitro cell experiment to detect

[0039] In the in vitro cell experiment, HepG2 (derived from American Type Culture Collection) cells were selected as experimental cells. The inventors treated HepG2 cells with different concentrations of 22(R)-hydroxycholesterol (abbreviated as 22(R)-HC), T09013171 and GW3965. For treatment methods, see HuangD, YangC, WangY, LiaoY, & HuangK. PARP-1 suppresses adiponectin expression through poly(ADP-ribosyl)ation of PPARgammaincardiacfibroblasts. Cardiovascularresearch, 2009, 81(1): 98-107.

[0040] HepG2 cells were stimulated with GW3965 (ii, 1 μmol / L, 3 μmol / L, 5 μmol / L) or niacin (iv, 1 μmol / L, 5 μmol / L, 10 μmol / L) for 24 hours, and the concentrations in the above brackets were final concentration.

[0041] PARP1 activity was detected using a PARP1 activity detection kit (purchased from Trevigen, produced in the United States, model number 4676-096-K). For specific methods, refer to the instructions of the k...

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Abstract

The invention relates to an application of 3-[3-[[[2-chloro-3-(trifluoromethyl) phenyl] methyl] (2,2-xenylethyl) amino] propoxy] phenylacetate (abbreviated as GW3965) as 1-type poly (ADP-ribose) synthetase inhibitor. GW3965 is an LXR agonist, and has no cytotoxic effects of common anti-tumor drugs or other 1-type poly (ADP-ribose) synthetase inhibitors as the cholesterol analogue, and the safety of GW3965 can be predicated. GW3965 can be widely applied as the medicine for treating cholesterol related diseases, including cardiovascular diseases, tumour and the like.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to 3-[3-[[[2-chloro-3-(trifluoromethyl)phenyl]methyl](2,2-biphenylethyl)amino]propoxy Application of base] phenylacetate hydrochloride as PARP1 inhibitor. Background technique [0002] 3-[3-[[[2-Chloro-3-(trifluoromethyl)phenyl]methyl](2,2-biphenylethyl)amino]propoxy]phenylacetic acid hydrochloride, The abbreviation is GW3965, the molecular weight is 618.51, and the chemical formula is C 33 h 31 CIF 3 NO 3 .HCl, CAS No. 405911-17-3. [0003] GW3965 belongs to the hydroxylated cholesterol analogues and has the effect of lowering cholesterol. In the current research, it is mainly used as an agonist of the liver X receptor (LXR), that is, to activate LXR, such as activating the gene LXRα (liver X receptor α subtype), so the above drugs are widely used in LXR-related research middle. [0004] Poly ADP-ribose synthase type 1, abbreviated as PARP1, is a ribozyme widely expressed in eukaryo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/195A61P35/00A61P9/00A61P43/00
Inventor 黄恺张冯筱罗希
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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