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Cdc42 inhibitor and application thereof

A technology of cdc42 and inhibitors, applied in the field of compounds, can solve the problem of no selective inhibitors of Cdc42 and achieve the effect of reducing accumulation

Active Publication Date: 2012-11-28
ONCO BIOMEDICAL TECH SUZHOU
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few effective Cdc42 selective inhibitors

Method used

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  • Cdc42 inhibitor and application thereof
  • Cdc42 inhibitor and application thereof
  • Cdc42 inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Virtual Screening of Cdc42 Inhibitors

[0030]Analysis of the three-dimensional structure of the Cdc42-ITSN complex revealed a major binding domain between the two molecules, the hydrogen bond between the Gln1380 residue and the Arg1384 residue in the ITSN molecule and between Asn39 and Phe37 on Cdc42, and the hydrogen bond in the ITSN molecule Two hydrophobic clusters between residues Leu1376, Met1379 and Thr1383 and between Phe56, Tyr64, Leu67 and Leu70 on Cdc42. In order to screen Cdc42 inhibitors, it is presumed that the binding pocket on the Cdc42 molecule is a structure formed by amino acid residues within a radius distance of 7A from the ITSN protein surface that binds to Cdc42. This contains 16 amino acid residues such as Thr35, Val36, Asn39, Phe56 and Asp57 in the Cdc42 protein molecule, such as Figure 1A-Figure 1C shown.

[0031] The Glide program was used to screen the small molecular compounds that could disrupt the connection between Cdc42 and ...

Embodiment 2

[0033] Embodiment 2: the synthesis of compound ZCL278:

[0034] ZCL278 can be synthesized by the following synthetic method, the following synthetic method is only for illustration, not limitation of the present invention, those skilled in the art can understand and imagine that other synthetic methods can be used to synthesize ZCL278, which also belongs to the protection scope of the present invention .

[0035] Reagents and conditions: (a) K 2 CO 3 , DMF (N, N-dimethylformamide), 70°C; (b) NaOH, dioxane (dioxane) / H 2 O; (c) SOCl 2 (thionyl chloride), DMF, reflux (reflux); (d) NaSCN (sodium thiocyanate), acetone (acetone), 0°C-rt; (e) 4-amino-N-(4,6-dimethylpyrimidin -2-yl)benzene-sulfonamide (4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide), 0°C-r.t.

[0036] The reaction formula is as follows:

[0037]

[0038] Compound 1 (4-bromo-2-chlorophenol) and ethyl 2-bromoacetate in K 2 CO 3 Nucleophilic substitution reaction in the presence can afford compound 2...

Embodiment 3

[0046] Embodiment 3: ZCL278 active characteristic

[0047] 1. ZCL278 inhibits Cdc42-mediated microspine formation

[0048] The effects of 30 candidate compounds on Cdc42-mediated microspike / filopodia formation were tested on serum-free mouse fibroblast Swiss 3T3 cells. Microspines / filopodia composed of fibroblast actin characterize Cdc42 activity. Such as Figure 2A As shown, a few micro spines (indicated by small arrows) and characteristic stress fibers mediated by RhoA (indicated by asterisks) can be seen at the edge of the cells in the control group. After the cells were briefly stimulated with 1 unit / mL of Cdc42 agonist (cytoskeleton company), the number of micro spines increased and the number of stress fibers decreased obviously. Adding the above agonists for 2 minutes, and then treating the cells with 50uM ZCL278 for 1 hour, ZCL278 significantly inhibited the formation of microthorns compared to the agonist alone. This result shows that the compound can be used as a...

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Abstract

The invention relates to a compound in a structure disclosed as Formula I, which can be used for preparing a Cdc42 inhibitor. Morphological analysis on filopodia, Western blot Cdc42 phosphorylation and downstream effector protein WASP analysis, cell wound healing test and formation test indicate that the compound provided by the invention can inhibit all processes into which Cdc42 participates, and effectively inhibit the action of Cdc42. The compound provided by the invention effectively inhibits cell functions into which actin participates, such as dictyosome tissue and cell movement.

Description

technical field [0001] The present invention relates to a compound, in particular to a Cdc42 inhibitor and application thereof. Background technique [0002] The cell division cycle protein Cdc42, a subclass of the Rho GTPase family of small G proteins, is an important regulatory protein for many cellular biological functions. First discovered in Saccharomyces cerevisiae, it is involved in cell polarization, and later recognized to play an important role in cytoskeleton reorganization, endocytic transport pathway of cells, cell cycle regulation and cell transcription. Like most GTPases, Cdc42 is activated by signaling through GDP exchange for GTP binding. The cycle between this nucleotide-restricted conformation of the Rho GTPase family is regulated by three important classes of proteins: guanine exchange factors (GEF), which catalyze the release of GDP and the binding of GTP; GTPase-activating proteins (GAP), which act as Negative regulator accelerates the hydrolysis of R...

Claims

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Application Information

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IPC IPC(8): C07D239/69A61K31/635A61P35/00A61P9/00A61P11/00A61P25/00
CPCC07C335/12C07D239/42C07D239/69A61K31/505A61P9/00A61P11/00A61P25/00A61P35/00A61P35/04A61P43/00
Inventor 陆群周虎臣陈燕华
Owner ONCO BIOMEDICAL TECH SUZHOU
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