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CN-122005537-A - Application of Phellinin O in preparing sensitizer of immune checkpoint inhibitor

CN122005537ACN 122005537 ACN122005537 ACN 122005537ACN-122005537-A

Abstract

The invention discloses an application of Phellinin O in preparing a sensitizer of an immune checkpoint inhibitor, and relates to the technical field of biological medicines. The invention also discloses a pharmaceutical composition for treating microsatellite stabilized tumor and a method for screening small molecule compounds for inducing microsatellite instability. The invention reduces the expression level of mismatch repair protein through the moracin O to promote the tumor to be transformed into a microsatellite instability state, thereby enhancing the sensitivity of MSS tumor to immunotherapy and providing a new therapeutic strategy for MSS tumor drug development.

Inventors

  • ZOU CHENGGANG
  • DUAN JIAHONG
  • CUI YONGYI
  • MA YICHENG

Assignees

  • 云南大学

Dates

Publication Date
20260512
Application Date
20260407

Claims (8)

  1. 1. Application of Phellinin O in preparing sensitizer for immune checkpoint inhibitor is provided.
  2. 2. The use of claim 1, wherein the sanguinin O promotes microsatellite instability in the tumor genome by reducing the expression level of mismatch repair protein.
  3. 3. The use according to claim 2, wherein the mismatch repair proteins comprise MSH2, MSH6 and PMS2 proteins.
  4. 4. The use of claim 1, wherein the doxin O is used to enhance the sensitivity of a microsatellite stabilized tumor to an immune checkpoint inhibitor.
  5. 5. The use of claim 4, wherein the microsatellite stabilized tumor is colorectal cancer.
  6. 6. The use according to claim 1, further comprising the use of a derivative of moracin O for the preparation of a sensitizer for an immune checkpoint inhibitor; the derivatives of the saminin O are compounds with the same functions, which are obtained by modification on the basis of the saminin O.
  7. 7. A pharmaceutical composition for the treatment of microsatellite stabilized tumors comprising the compound of claim 1, moracin O and an immune checkpoint inhibitor.
  8. 8. A method for screening small molecule compounds for inducing microsatellite instability, characterized in that candidate small molecule compounds are incubated with a tumor cell line with high expression of mismatch repair protein, the effect on the level of mismatch repair protein is detected, and the positive control is the samin O as defined in claim 1.

Description

Application of Phellinin O in preparing sensitizer of immune checkpoint inhibitor Technical Field The invention relates to the technical field of biological medicines, in particular to application of Phellinin O in preparation of a sensitizer of an immune checkpoint inhibitor. Background Microsatellite instability (MSI) is a phenomenon of accumulation of DNA repair errors due to defects in the mismatch repair (MMR) system. Tumors in MSI status often exhibit higher mutational burden, and therefore MSI-H tumors often respond better to immune checkpoint inhibitors (e.g., PD-1, PD-L1). However, many microsatellite stabilized (MSS) tumors do not exhibit high levels of mutational burden and therefore respond poorly to immunotherapy. Key proteins in the mismatch repair (MMR) system (e.g. MSH6, MSH2, PMS2, MLH 1) play an important role in maintaining DNA sequence stability. Studies show that inhibiting the expression of MMR protein can effectively induce MSI to occur, so that MSS tumor has higher sensitivity to immunotherapy. The existing research is mostly performed by intervention of MMR functions through gene editing, but naturally-derived small molecules are ideal choices for drug development due to the structural diversity and low toxicity advantages, however, no natural compounds have been reported at present to induce MSI states by reducing MSH2, MSH6 and PMS2 levels. Disclosure of Invention In order to solve the technical problems, the invention aims to provide the application of the morin O in preparing the sensitizer of the immune checkpoint inhibitor, and the invention promotes the tumor to be converted into a microsatellite instability state by reducing the expression level of mismatch repair protein through the morin O, thereby enhancing the sensitivity of MSS type tumor to immunotherapy and providing a new treatment strategy for MSS tumor drug development. The technical scheme for solving the technical problems is as follows, and the application of the morin O in preparing the sensitizer of the immune checkpoint inhibitor is provided. Further, moracin O promotes tumor transformation to microsatellite instability status (MSI) by reducing the expression level of mismatch repair (MMR) proteins. Further, mismatch repair (MMR) proteins include MSH2, MSH6 and PMS2 proteins. Further, the moracin O is used to enhance the sensitivity of microsatellite stabilized (MSS) tumors to immune checkpoint inhibitors. Further, microsatellite stabilized (MSS) tumors are colorectal cancers. Further, the application also comprises the application of the derivatives of the morin O in preparing the sensitizer of the immune checkpoint inhibitor; the derivatives of the saminin O are compounds with the same functions, which are obtained by modification on the basis of the saminin O. The invention also provides a pharmaceutical composition for treating microsatellite stabilized tumor, which is characterized by comprising the moracin O and an immune checkpoint inhibitor. Further, the immune checkpoint inhibitor is PD-1. The invention also provides a method for screening the small molecule compounds for inducing the microsatellite instability state, which incubates candidate small molecule compounds with a tumor cell line with high expression of mismatch repair protein, detects the influence of the candidate small molecule compounds on the level of the mismatch repair protein, and takes the samin O as a positive control. The invention has the following beneficial effects: The invention provides research application of natural small molecular mulberrin O as an MMR protein inhibitor, which successfully converts MSS type tumors into MSI-like phenotypes by reducing MMR protein expression and increasing mutation load. The discovery not only provides a new strategy for the immune therapy sensitization of MSS tumors, but also provides a theoretical basis for the combined treatment of tumor drugs. Drawings FIG. 1 is a diagram showing the result of verification of inhibition of mismatch repair protein by Phellin O, wherein A is an immunoblotting diagram of HT29 cells, B is a comparison diagram of MMR protein expression amount of HT29 cells, C is an immunoblotting diagram of CT26 cells, and D is a comparison diagram of MMR protein expression amount of CT26 cells. FIG. 2 is a graph of DNA damage marker detection results, wherein A is a fluorescent staining graph, B is a gamma-H2 AX positive duty ratio graph, C is an immunoblotting graph, and D is a gamma-H2 AX protein relative expression level graph. FIG. 3 shows peak patterns of HT29 and CT26 cell microsatellite loci, wherein A is the peak pattern of human standard microsatellite loci BAT26 and NR24, and B is the peak pattern of mouse microsatellite loci mBat, mBat, mBat-30. Fig. 4 is a diagram of toxicity detection and dose results of the moracin O, wherein a is a cell viability comparison diagram and B is an immunoblot diagram. Detailed Description The principles and features of the presen