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CN-122005808-A - Application of targeted FIGNL-FIRRM-MACIR complex inhibitor in preparation of tumor drugs and composition thereof

CN122005808ACN 122005808 ACN122005808 ACN 122005808ACN-122005808-A

Abstract

The invention provides an application of an inhibitor of a targeted FIGNL-FIRRM-MACIR complex in preparing a tumor medicament and a composition thereof. This study identified MACIR as the bridge-like adapter subunit of the FIGNL1-FIRRMAAA + atpase complex. MACIR promote the unfolding of FIGNL-mediated RAD51 filamentous structures by directly combining FIRRM and DNA, thereby promoting repair of inter-strand cross-linking (ICLs) damage of DNA induced by aldehydes or platinum drugs and maintaining genome stability. Pharmacological inhibition of the FIGNL-FIRRM-MACIR complex, including the use of two inhibitors 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid and 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide against the FIGNL-FIRRM-MACIR complex, significantly enhanced the cytotoxic effects of platinum-based drugs in ovarian cancer.

Inventors

  • CHEN YIFAN
  • GAO HUAFANG
  • 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 (13)

  1. 1. The application of the targeted FIGNL-FIRRM-MACIR complex inhibitor in preparing tumor medicaments.
  2. 2. The use according to claim 1, wherein the tumor is a malignant tumor that relies on ICL injury mechanisms to develop resistance to platinum-based drugs.
  3. 3. The use according to claim 1, wherein the tumor is ovarian cancer, non-small cell lung cancer, breast cancer or bladder cancer.
  4. 4. Use according to claim 1, wherein the inhibitor is 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid or 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide.
  5. 5. The application of an inhibitor of a targeted inhibition FIGNL-FIRRM-MACIR complex in preparing a platinum chemotherapy combined drug for tumors is characterized in that the combined drug comprises the inhibitor and a platinum chemotherapy drug.
  6. 6. The use according to claim 5, wherein the platinum-based chemotherapeutic agent is one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin.
  7. 7. The use according to claim 5, wherein the inhibitor is 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid or 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide.
  8. 8. A combination pharmaceutical composition for platinum chemosensitization of tumors, which is characterized by comprising an inhibitor of FIGNL-FIRRM-MACIR complex and a platinum chemotherapeutic drug, and further comprising a pharmaceutically acceptable carrier, diluent or excipient.
  9. 9. The combination of claim 8, wherein the platinum-based chemotherapeutic agent is one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin.
  10. 10. The combination of claim 8, wherein the inhibitor is 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid or 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide.
  11. Use of 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid or 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide in the manufacture of a medicament for treating tumors.
  12. 12. The use according to claim 11, wherein the tumour is a malignancy that relies on ICL damage mechanisms to develop resistance to platinum drugs.
  13. 13. The use according to claim 12, wherein the tumor is ovarian cancer, non-small cell lung cancer, breast cancer or bladder cancer.

Description

Application of targeted FIGNL-FIRRM-MACIR complex inhibitor in preparation of tumor drugs and composition thereof Technical Field The invention relates to the field of biotechnology, in particular to application of an inhibitor of a targeted FIGNL-FIRRM-MACIR complex in preparation of tumor medicaments 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. Since AAA + atpase unfolding enzymes (e.g. classical p 97) typically rely on multiple adaptor proteins to recognize and remodel different substrates, exploring the presence of bridge-like adaptor proteins to specifically enhance the effect of FIGNL-FIRRM on RAD51 filaments is of great research value and helps to develop novel therapeutic drugs 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 of a targeted FIGNL1-FIRRM-MACIR complex in preparing tumor medicaments. 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 inhibitor is 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid or 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide. In one embodiment, the invention provides the use of an inhibitor of a targeted inhibition FIGNL1-FIRRM-MACIR complex in the preparation of a platinum chemotherapeutic combination for a tumor, the combination comprising the inhibitor and a platinum 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 platinum chemosensitization comprising an inhibitor of the FIGNL-FIRRM-MACIR complex and a platinum chemotherapeutic agent, and further comprising a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the present invention provides the use of 4- {2- [ (5-chloro-2-methoxyanilino) carbonyl ] anilino } -4-oxobutanoic acid or 2- { [5- (2-ethoxyethyl) -4-hydroxy-6-oxo-1, 6-dihydro-2-pyrimidinyl ] thio } -N- (3-methoxyphenyl) acetamide in the manufacture of a medicament for treating tumors. To identify FIGNL-FIRRM potential adaptor proteins, we performed this study and successfully locked C5orf30 as a candidat