Compounds for treatment of cancer and epigenetics

A compound and alkyl technology, applied in the field of quinoline and 5,6,7,8-tetrahydroacridine derivatives, can solve the problems of undisclosed anti-proliferation cell activity and achieve high efficacy

Inactive Publication Date: 2018-08-17
AGENCY FOR SCI TECH & RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the reported molecule is active against SMYD3, no antiproliferative cell activity is disclosed

Method used

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  • Compounds for treatment of cancer and epigenetics
  • Compounds for treatment of cancer and epigenetics
  • Compounds for treatment of cancer and epigenetics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0361] list of abbreviations used

[0362]

[0363] Bioassay Materials and Methods

[0364] SMYD3 biochemical assay

[0365] The SMYD3 enzymatic assay was developed using Promega's methyltransferase-Glo™ reagent. In the assay, SMYD3 catalyzes the methylation of MAP3K2 peptide substrates by transferring a methyl group from SAM to MAP3K2 peptide and further converts SAM to SAH. SMYD3 methyltransferase activity was measured based on the amount of SAH produced from the reaction by using a coupled enzyme that converts SAH to ATP. The MTase-Glo detection solution then catalyzes the formation of light from ATP.

[0366] for IC 50 For determination, compounds were incubated with 0.4 μM SMYD3 enzyme for 30 min in low volume 384-well plates. SAM and MAP3K2 peptides were added at final concentrations of 1.0 μM and 10 μM and further incubated for 30 min at room temperature before adding MTase Glo and detection reagents. Reaction signals were detected using a microplate reader (...

Embodiment 2

[0380] SMYD3 biochemical assay

[0381] The ability of compounds to inhibit the catalytic function of SMYD3 was tested using the MTase assay by using MAP3K2 as the peptide substrate. Said compounds were found to inhibit the methyltransferase activity of SMYD3. The effect of the compounds on the methyltransferase activity of SMYD3 using the MAP3K2 peptide as substrate can be found in Figure 1 (Compounds A066; A074; B019; A088). The data have been summarized in Table 1.

[0382] Table 1. Biochemical ICs of SMYD3 Inhibitors 50 summary.

[0383] compound

Embodiment 3

[0385] SMYD3 compounds inhibit the proliferation of different cancer cells

[0386] The antiproliferative effect of SMYD3 inhibition was explored in different cancer cell lines. Dose-response curves are shown in FIG. 2 . All cell lines with GI ranging from 11 to 50 μM 50 Values ​​are in response to SMYD3 inhibitors. A subset of the data is summarized in Table 2.

[0387] Table 2. Summary of antiproliferative activity of SMYD3 inhibitors in different cancer cell lines (compounds A066; A074; B019; A088).

[0388]

[0389] *ND: not determined

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Abstract

The present invention relates to quinolines and 5,6,7,8-tetrahydroacridines of the formula (I) wherein Z1, Z2, X, R1 to R8 and Y are defined as described in the specification, or a pharmaceutically acceptable form or prodrug thereof, that are inhibitors of methyl transferases such as protein lysine methyltransferases and more particularly SMYD3. The present invention also relates to the methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of disorders / conditions / diseases involving, relating to or associated with enzymes having methyl transferase activities / functions and / or via unspecified / multi-targeted mechanisms.

Description

technical field [0001] The present invention relates generally to quinoline and 5,6,7,8-tetrahydroacridine derivatives, processes for their preparation, pharmaceutical compositions containing these compounds and the use of these compounds in the treatment of disorders / conditions / diseases, so The disorder / condition / disease involves, is related to or is associated with an enzyme having methyltransferase activity. Background technique [0002] The genomes of eukaryotic organisms are tightly packaged into chromatin, which forms the structural basis of nuclear processes associated with gene activity. The nucleosome is the smallest structural unit of chromatin, in which 146 base pairs of DNA are wrapped around an octamer of core histones. Histones undergo several post-translational covalent modifications, and this plays a key role in controlling gene transcription within cells. Among the various histone modifications, methylation of lysine residues appears to play a particularly...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07D295/182A61K31/473C07D471/02A61K31/4709A61K31/496A61K31/499A61K31/4995A61P35/00C07D471/04C07D471/08C07D471/10
CPCA61K31/496A61K31/506A61K45/06A61P35/00C07D215/48C07D219/04C07D221/16C07D401/04C07D401/06C07D401/10C07D401/12C07D401/14C07D405/04C07D405/14C07D409/04C07D413/04C07D413/06C07D413/12C07D413/14C07D417/04C07D417/14C07D471/04C07D471/08A61K2300/00
Inventor 符基豪A·鲍尔森T·H·凯勒刘思思谢青山洪振扬黄楚惠
Owner AGENCY FOR SCI TECH & RES
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