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CN-122005819-A - Application of inhibitor for targeted inhibition MACIR of expression or function in preparation of tumor chemosensitizer and composition thereof

CN122005819ACN 122005819 ACN122005819 ACN 122005819ACN-122005819-A

Abstract

The application provides application of an inhibitor for targeted inhibition MACIR of expression or function in preparation of a tumor chemotherapy sensitizer and a composition thereof, wherein the tumor chemotherapy sensitizer is specifically a tumor platinum chemotherapy sensitizer. The application identifies MACIR as a novel adapter protein of FIGNL-FIRRM unfolding enzyme, clarifies the role of the novel adapter protein in the dissociation of RAD51 filiform structures, and reveals MACIR as a key protein in a DNA repair path aiming at DNA inter-strand crosslinking (ICLs) damage, and can influence the sensitivity of tumor cells to platinum drugs.

Inventors

  • GAO HUAFANG
  • CHEN YIFAN
  • WANG WEIBIN
  • ZHOU TAO

Assignees

  • 国家卫生健康委科学技术研究所

Dates

Publication Date
20260512
Application Date
20260409

Claims (15)

  1. 1. The application of an inhibitor for targeted inhibition MACIR expression or function in preparing tumor chemosensitizer.
  2. 2. The use according to claim 1, wherein the tumor chemosensitizer is a tumor platinum chemosensitizer.
  3. 3. The use according to claim 1 or 2, wherein the inhibitor is one or more of a MACIR-targeted siRNA, shRNA, antisense oligonucleotide, CRISPR/Cas system, monoclonal antibody, small molecule compound or polypeptide inhibitor.
  4. 4. The use according to claim 1 or 2, wherein the inhibitor functions by at least one of blocking MACIR interaction with FIRRM, inhibiting the DNA binding capacity of MACIR, or down-regulating the protein expression level of MACIR.
  5. 5. The use according to claim 1 or 2, wherein the tumour is a malignancy which relies on ICL damage mechanisms to develop resistance to platinum drugs.
  6. 6. The use according to claim 5, wherein the tumor is ovarian cancer, non-small cell lung cancer, breast cancer or bladder cancer.
  7. 7. The use of an inhibitor which targets to inhibit MACIR expression or function in the manufacture of a combination of a tumor chemotherapeutic, wherein the combination comprises the inhibitor and a platinum chemotherapeutic.
  8. 8. The use according to claim 7, wherein the platinum-based chemotherapeutic agent is one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin.
  9. 9. The use according to claim 7, wherein the tumor is a malignant tumor that relies on ICL injury mechanisms to develop resistance to platinum-based drugs.
  10. 10. The use according to claim 9, wherein the tumor is ovarian cancer, non-small cell lung cancer, breast cancer or bladder cancer.
  11. 11. A combination pharmaceutical composition for tumor chemosensitization, comprising an inhibitor that targets the inhibition MACIR of expression or function and a platinum-based chemotherapeutic agent, and further comprising a pharmaceutically acceptable carrier, diluent, or excipient.
  12. 12. The composition of claim 11, wherein the inhibitor is one or more of a MACIR-targeted siRNA, shRNA, antisense oligonucleotide, CRISPR/Cas system, monoclonal antibody, small molecule compound, or polypeptide inhibitor.
  13. 13. The composition of claim 11, wherein the platinum-based chemotherapeutic agent is one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin.
  14. 14. The composition of claim 11, wherein the tumor is a malignancy that relies on ICL injury mechanisms to develop resistance to platinum-based drugs.
  15. 15. The composition of claim 14, wherein the tumor is ovarian cancer, non-small cell lung cancer, breast cancer, or bladder cancer.

Description

Application of inhibitor for targeted inhibition MACIR of expression or function in preparation of tumor chemosensitizer and composition thereof Technical Field The invention relates to the field of biotechnology, in particular to application of an inhibitor for targeted inhibition MACIR of expression or function in preparation of tumor platinum chemosensitizer and a composition thereof. Background Inter-strand DNA cross-linking (ICLs) is a serious class of genomic DNA damage that can be induced by intracellular metabolic byproducts or exogenous deleterious chemicals, including aldehydes and platinum-based drugs. ICLs can simultaneously block DNA replication and RNA transcription, thereby resulting in DNA strand breaks and genomic instability. To cope with this injury, the cells evolved a specific repair mechanism-Vanconi anemia (FanconiAnemia, FA) pathway. This pathway coordinates the repair of ICL by a multi-step process, including activation of FA core complex, recruitment of structure-specific endonucleases to "unhook" the cross-linked structure, and repair of the consequent DNA Double Strand Breaks (DSBs) by Homologous Recombination (HR). Defects in the FA pathway can severely impair ICL repair efficiency and can lead to fanconi anemia, dysplasia, immune system disorders, or tumorigenesis. On the other hand, platinum-based chemotherapeutics treat a variety of malignancies, including ovarian cancer, by inducing accumulation of ICL lesions. In the FA pathway, the recombinase RAD51 mediates homology search, DNA pairing and strand invasion by forming nucleoprotein filaments (nucleoproteinfilaments) on single-stranded DNA (ssDNA), playing a central role in HR repair. Therefore, elucidation of molecular mechanisms that regulate RAD51 nuclear protein silk assembly and dissociation is of great importance for understanding ICL repair, maintenance of genomic stability, tumorigenesis, and chemotherapy reactions. The presently reported RAD51 regulatory mechanisms can be broadly divided into positive and negative. For example, classical cancer suppressing factors BRCA2 and BRCA1 promote assembly of RAD51 filamentous structures and enhance homologous DNA pairing. When RAD51 completes its function, helicases such as RTEL1, BLM and RECQ5 can act as anti-recombinases to dissociate the RAD51 filamentous structure in time. Notably, we and other research teams have recently discovered a novel class of anti-recombinant enzymes-FIGNL-FIRRM (also known as C1orf 112) complex, which acts by a mechanism different from all previously known RAD51 antagonists. The catalytic subunit FIGNL of the complex belongs to AAA+ATPase family, can form hexamer ring structure and combine with N end tail of RAD51, and finally realize dissociation of RAD51 filiform structure by protein unfolding mechanism through inducing conformational remodelling. Whereas AAA + atpase unfolding enzymes (e.g. classical p 97) typically rely on multiple adaptor proteins to recognize and remodel different substrates, exploring the presence or absence of bridge-like adaptor proteins to specifically enhance the effect of FIGNL-FIRRM on RAD51 filamentous structures is of great research value and helps to develop new strategies targeting this regulatory axis to sensitize tumor chemotherapy. Disclosure of Invention In order to solve the problems, the invention provides an application of an inhibitor for targeted inhibition MACIR of expression or function in preparation of tumor chemosensitizer. In one embodiment, the tumor chemosensitizer is a tumor platinum chemosensitizer. In one embodiment, the inhibitor is one or more of a MACIR-targeted siRNA, shRNA, antisense oligonucleotide, CRISPR/Cas system, monoclonal antibody, small molecule compound, or polypeptide inhibitor. In one embodiment, the inhibitor functions by at least one of blocking MACIR interactions with FIRRM, inhibiting the DNA binding capacity of MACIR, or down-regulating the protein expression level of MACIR. In one embodiment, the tumor is a malignancy that relies on ICL injury mechanisms to develop resistance to platinum-based drugs. In one embodiment, the tumor is ovarian cancer, non-small cell lung cancer, breast cancer, or bladder cancer. In one embodiment, the invention provides the use of an inhibitor that targets inhibition MACIR of expression or function in the manufacture of a combination of tumor chemotherapy comprising the inhibitor and a platinum-based chemotherapeutic. In one embodiment, the platinum-based chemotherapeutic agent is one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin. In one embodiment, the invention provides a combination pharmaceutical composition for tumor chemosensitization comprising an inhibitor that targets inhibition MACIR of expression or function and a platinum-based chemotherapeutic agent, and further comprising a pharmaceutically acceptable carrier, diluent, or excipient. To identify FIGNL-FIRRM potential adapter proteins, this study was con