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Novel PKC theta small-molecule inhibitor for inhibiting graft-versus-host diseases

A small molecule inhibitor, graft-versus-host technology, applied in the field of biomedicine, can solve the problems of low knockout efficiency, unsatisfactory number and quality of T cells, and many uncontrollable factors, to promote promotion and industrialization, The effect of promoting clinical application

Active Publication Date: 2015-11-25
安萌得医药科技(上海)有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The current CAR-T therapy is a "personalized" therapy. The cell products come from the patient himself, and cannot be "off-the-shelf", but can only be "made and used". Not only is the operation complicated, but there are many uncontrollable factors. The key problem is that 90% of patients are unable to receive CAR-T therapy due to their own T cell deficiency, especially because they have often received chemotherapy and immunosuppressant therapy before CAR-T therapy.
However, the preparation of allogeneic CAR-T by knocking out TCR currently encounters technical bottlenecks such as low knockout efficiency, and it is expected that it will not be used in clinical practice within a few years

Method used

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  • Novel PKC theta small-molecule inhibitor for inhibiting graft-versus-host diseases
  • Novel PKC theta small-molecule inhibitor for inhibiting graft-versus-host diseases
  • Novel PKC theta small-molecule inhibitor for inhibiting graft-versus-host diseases

Examples

Experimental program
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Effect test

Embodiment 1

[0077] Example 1: Inhibitory effect of FL-1507 on GVHD induced by allogeneic T cell transplantation. We treated T cells of C57BL / 6 mice with FL1507 or cosolvent for 24 hours (0.5x10 6 ), infused into BALB / c mice irradiated with a lethal dose of radioisotope, and observed and detected the ratio of spleen cells to transplanted T cells on the 4th and 14th day respectively, and determined the survival curve of the mice. The results showed that the GVHD induced by T cells treated with FL-1507 was significantly lower than that of the control group. The survival rate of mice in the FL-1507 group was also significantly higher than that in the control group. Image 6 shown.

[0078] At the same time, refer to Figure 5 As shown, FL-1507 significantly inhibited the expression of transcription factor RelA and cytokine IL-2 caused by CD3 / 28 activation of TCR. Therefore, by inhibiting TCR signal transduction, FL-1507 has an excellent inhibitory effect on GVHD caused by allogeneic T cel...

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Abstract

The invention discloses a novel PKC theta small-molecule inhibitor. The PKC theta small-molecule inhibitor is FL-1507, and the molecular formula of the PKC theta small-molecule inhibitor is as follows. The PKC theta small-molecule inhibitor inhibits the TCR receptor signal transduction on T cells by inhibiting PKC theta so as to further inhibit the production of TCR-mediated GBHD. The PKC theta small-molecule inhibitor can inhibit GVHD caused by homologous allograft CAR-T treatments and promote the popularization and industrialization of the homologous allograft CAR-T. Meanwhile, the PKC theta small-molecule inhibitor can also be used to prevent the GVHD caused by allograft bone marrow suppression.

Description

technical field [0001] The present invention relates to a novel small molecule inhibitor of PKCθ that inhibits graft-versus-host disease (GVHD) in the field of biomedicine, in particular to a small molecule that has a strong inhibitory effect on the signal transmission of somatic cell antigen receptor (TCR) Compound for the prevention of potentially fatal GVHD during allogeneic CAR-T therapy. Background technique [0002] Chimeric antigen receptor T cell immunotherapy (CAR-T therapy) represents the forefront of current tumor immune cell therapy technology, and has achieved great success in clinical trials of acute lymphoblastic leukemia. Its basic principle is to use the patient's own T cells to specifically recognize tumor-associated antigens after modification by chimeric antigen receptors, so that the targeting, killing activity and persistence of effector T cells are better than conventionally used immune cells. High, and can overcome the tumor local immunosuppressive m...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61P37/06
Inventor 范国煌
Owner 安萌得医药科技(上海)有限公司
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