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Benzimidazopyrazine-3-carboxamide targeting A2A and tumor immune function thereof

A tumor-targeting technology, applied in the field of medicine, can solve problems such as benefiting patients, and achieve the effect of enhancing effect, inhibiting cAMP accumulation, and enhancing killing effect.

Active Publication Date: 2022-05-27
SUN YAT SEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Cancer immunotherapy based on immune checkpoint inhibition or adoptive cell therapy has revolutionized cancer treatment, yet a large proportion of patients do not benefit from such treatments

Method used

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  • Benzimidazopyrazine-3-carboxamide targeting A2A and tumor immune function thereof
  • Benzimidazopyrazine-3-carboxamide targeting A2A and tumor immune function thereof
  • Benzimidazopyrazine-3-carboxamide targeting A2A and tumor immune function thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 1-Amino-N-(pyridin-2-ylmethyl)benzo[4,5]imidazo[1,2-a]pyrazine-3-carboxamide small molecule compound (LDH-E- 4) Preparation

[0037] The structure of LDH-E-4 is shown below:

[0038]

[0039] The preparation of this compound comprises the following steps:

[0040] (1) preparation of compound shown in formula 3:

[0041]

[0042] According to the above reaction formula, the compound shown in formula 1 (1,2-phenylenediamine, 3.2 g, 30 mmol) and 50 mL of acetic acid (AcOH) were added to the reaction flask at room temperature, and the starting materials were slowly added after cooling in an ice bath, That is, the compound represented by formula 2 (methyl 2,2,2-trichloroiminoacetate, 4 mL, 30 mmol) was added and stirred at room temperature for 2 hours, and TLC showed that the reaction was completed. After the reaction, the reactant was filtered, and the obtained filter cake was washed with water (3×25 mL) and dried under vacuum to obtain the compound repre...

Embodiment 2

[0077] Example 2 LDH-E-4 specifically targets A 2A Research on the characteristics of R

[0078] (1) Cell culture

[0079] The A2A-HEK293 and A1-HEK293 (HEK293 cells used in this experiment were purchased from ATCC, and the construction of the overexpressed cell line is based on "Borodovsky, A., et al., Small molecule AZD4635 inhibitor of A2ARsignaling rescues immune cell function including CD103+dendritic" cellsenhancing anti-tumor immunity. Journal for ImmunoTherapy of Cancer, 2020.8(2):p.e000417."), MBA-MD-231 (purchased from ATCC) cells were cultured in cells containing 10% fetal bovine serum and 1% double antibody (penicillin and Streptomycin) in DMEM medium, 4T1 and PBMC cells were cultured in RPIM-1640 medium containing 10% fetal bovine serum and 1% double antibody (penicillin and streptomycin), and the above cells were placed at 37°C, 5%CO 2 cultured in a cell incubator.

[0080] (2) Compound pair A 2A R and A 1 Affinity testing for R

[0081] 1) Preparation of ...

Embodiment 3

[0107] Example 3 Study on the characteristic of LDH-E-4 inhibiting the accumulation of cAMP

[0108] (1) Compound and buffer configuration

[0109] Assay buffer was prepared containing 1 x HBSS (Sigma), 0.1% BSA (Perkin Elmer), 20 mM HEPES (Gibco) and 100 nM IBMX (Sigma). Use Simulationbuffer to configure 8× test compound stock solutions (10 -4 ,10 -5 ,10 -6 , 10 -7 ,10 -8 ,10 -9 ,10 -10 M) and 8x CGS21680 stock solution (50 nM). Prepare 20× cAMP-d2 and 20× anti-cAMP-Eu3+ detection reagent solutions using Lysis & Detection Buffer lysis buffer.

[0110] (2) HTRF method to test intracellular cAMP content

[0111] The HEK293-A 2A Cells were seeded in 384-well plates containing 38,000 cells per well and 15 μL of assay buffer. 2.5 μL of test compound solutions were added to designated wells of the above 384-well plate and incubated at 37°C for 10 minutes. Then, 2.5 μL of CGS21680 stock solution was added to the 384-well plate, and incubated at 37° C. for another 30 minu...

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PUM

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Abstract

The invention belongs to the technical field of medicines, particularly relates to A2A-targeting benzimidazopyrazine-3-formamide and a tumor immune function thereof, and discloses a subtype selective adenosine A2A receptor antagonist, namely a 1-amino-N-(pyridine-2-yl methyl) benzo [4, 5] imidazopyrazine-3-formamide small molecule compound, of which the structure is shown as a formula (I). Researches find that the small molecule compound can specifically target A2AR, inhibit cAMP accumulation, promote release of immune cell cytokines, enhance killing of immune cells on tumor cells in co-culture and enhance the tumor immunotherapy effect. The polypeptide shows an obvious tumor immunoenhancement effect in molecular level, cellular level and cancer mouse models, and is expected to be applied to tumor immunotherapy.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to targeting A 2A Benzimidazopyrazine-3-carboxamide and its tumor immune function. Background technique [0002] Cancer immunotherapy based on immune checkpoint inhibition or adoptive cell therapy has revolutionized the way cancer is treated, yet a large proportion of patients do not benefit from such treatments. Multiple redundant and non-redundant immunosuppressive pathways active in the tumor microenvironment (TME) may partially explain the low response rate of current immune checkpoint therapy. A key mechanism of cancer immune evasion is the production of high levels of immunosuppressive adenosine within the TME. A large amount of adenosine in the tumor microenvironment can inhibit the proliferation and maturation of immune cells such as T cells and NK cells and the production of immune cytokines, thereby causing immune damage to the body and promoting the growth o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P15/14A61P35/00A61P37/04
CPCC07D487/04A61K31/4985A61P15/14A61P35/00A61P37/04
Inventor 胡文浩丁文刘书豪张芷菁吴琳娜郭银锋黄炜枫张小雷史滔达雷金平
Owner SUN YAT SEN UNIV
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