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CN-122005555-A - Use of STK31 kinase inhibitor ciclopirox compound for treating pancreatic ductal adenocarcinoma

CN122005555ACN 122005555 ACN122005555 ACN 122005555ACN-122005555-A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a ciclopirox compound in medicines for treating KRAS G12D mutation-induced cancers, wherein the cancers comprise pancreatic ductal adenocarcinoma and colorectal cancer. The compound can obviously inhibit the activity of KRAS mutant pancreatic cancer cells, has weak inhibition on KRAS wild type cells, and shows potential targeted therapeutic advantages. Animal experiment results show that the ciclopirox compound can effectively inhibit tumor growth and down regulate expression of phosphorylated STK31 protein. The invention has definite components and simple and convenient preparation, and provides a new strategy for overcoming pancreatic cancer drug resistance.

Inventors

  • LIU YUTING
  • QI JIAN
  • LI BO
  • LIN JIAHUI
  • KE LINGLING
  • WU HUIXIAN
  • LUO TINGTING
  • TIAN TIAN

Assignees

  • 中山大学附属第七医院(深圳)

Dates

Publication Date
20260512
Application Date
20260202

Claims (10)

  1. 1. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of KRAS G12D mutation-induced cancer, The compound of formula (I), Wherein R 1 is H, alkyl of C 1 -C 4 , R 2 is cyclohexyl or its substituent, Including pancreatic ductal adenocarcinoma and colorectal cancer.
  2. 2. The use according to claim 1, wherein the pancreatic cancer is KRAS G12D mutant pancreatic ductal adenocarcinoma.
  3. 3. The use according to claim 1, wherein the compound inhibits the activity of KRAS G12D mutant pancreatic ductal adenocarcinoma cells by down-regulating the expression of phosphorylated STK31 protein, thereby exerting pharmaceutical activity.
  4. 4. The use according to claim 1, characterized in that the amount of said compound is 30mg/kg ± 10%.
  5. 5. The use according to any one of claims 1-4, wherein the medicament further comprises at least one of an excipient, a buffer and a compatible carrier.
  6. 6. The use according to any one of claims 1 to 4, wherein the compound of formula (I) has the (R) -or (S) -configuration.
  7. 7. The use according to any one of claims 1-4, wherein the medicament further comprises a second active ingredient selected from at least one of an immune checkpoint inhibitor, a chemotherapeutic agent and an anti-inflammatory agent.
  8. 8. The use according to any one of claims 1 to 4, wherein the medicament is in the form of a tablet, capsule, injection or inhalant.
  9. 9. The use according to claim 5, wherein the compatible carrier is microcrystalline cellulose, lactose or polyethylene glycol.
  10. 10. The use according to any one of claims 1 to 4, wherein the medicament is administered orally or intravenously.

Description

Use of STK31 kinase inhibitor ciclopirox compound for treating pancreatic ductal adenocarcinoma Technical Field The invention belongs to the technical field of medicines, and particularly relates to a novel application of a STK31 kinase inhibitor ciclopirox compound in treating pancreatic duct adenocarcinoma. Background Pancreatic cancer is one of common malignant tumors of digestive system, and has the characteristics of hidden onset, high malignant degree, extremely poor prognosis and the like. About 90% of pancreatic cancers are pancreatic ductal adenocarcinomas, with 5-year survival rates below 10%. According to research reports, more than 10 tens of thousands of patients with pancreatic ductal adenocarcinoma are diagnosed each year in China. Currently, the treatment methods of pancreatic duct adenocarcinoma mainly include surgery (such as pancreas-duodenum resection, distal pancreas resection, total pancreas resection), chemotherapy (such as FOLFIRONOX, mFOLFIRINOX), radiotherapy, interventional therapy (such as trans-arterial infusion chemotherapy, ablation therapy, PTCD, biliary stent implantation, etc.), support therapy, and the like. Pancreatic ductal adenocarcinomas are "cold tumors" that have characteristics of immunosuppressive microenvironment, low immunogenicity, dense stroma, etc., which make them generally poorly responsive to traditional immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 or CTLA-4 inhibitors). At present, no treatment method can effectively improve the survival rate of pancreatic duct adenocarcinoma patients. For patients with advanced pancreatic cancer, chemotherapy remains the primary means. Gemcitabine is the first line drug for the treatment of pancreatic cancer, but resistance is widespread, with more than 80% of PDAC patients being resistant to gemcitabine. Many of the current anti-tumor drug development and treatment strategies are directed to aberrant phosphorylation processes. In 1982, HRAS and KRAS in the RAS gene family were found to be the first human cancer genes, with KRAS later identified as one of the most commonly mutated oncogenes. KRAS is the most frequent mutation in all RAS genes, accounting for about 80% of all RAS mutations. Notably, RAS mutations have significant tissue specificity, the most common and fatal types of cancer, such as colorectal cancer (CRC), pancreatic Ductal Adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC), all are closely related to KRAS mutations (43%, 90%, and 31%, respectively). However, it has taken up to 40 years to develop clinically effective inhibitors against RAS mutant cancers. In 2013, shokat and colleagues found a pocket for forming a medicine on KRAS, which lays a solid foundation for later medicine development, and the current medicine for KRAS gene mutation mainly aims at KRAS G12C (glycine mutation is cysteine) and acts as an inhibitor for the medicine. Notably, KRAS G12D (51%) and KRAS G12V (30%) are the more common mutation types in PDACs, whereas KRAS G12C occurs at only 2%. Although mutations in KRAS G12D and KRAS G12C occur at amino acid 12, there are significant differences in structure, molecular mechanisms, tumor biological properties, and response to KRAS inhibitors. The prognosis of KRAS G12D mutant PDAC patients is worse than that of other mutant patients, particularly in patients with shortened survival, enhanced invasiveness of the tumor, poor therapeutic response to conventional chemotherapeutic drugs, and high risk of postoperative recurrence. In KRAS G12D, amino acid 12 is changed from glycine to aspartic acid (ASPARTIC ACID) with a negatively charged carboxyl group (-COOH) on its side chain. Such groups lack the nucleophilic nature of the cysteine thiol group and therefore cannot form stable covalent bonds, so the G12D mutated KRAS is generally insensitive to KRAS G12C-specific inhibitors. Unfortunately, these novel KRAS inhibitors have been reported to potentially lead to new KRAS mutants (e.g., KRAS Y96D/NRAS Q61L/NRAS Q61R, etc.) in lung and colorectal cancer patients, activating multiple downstream signaling pathways, and even altering the pathological type of tissue, leading to acquired drug resistance responses. Therefore, developing a new solution capable of effectively inhibiting KRAS signaling pathway and overcoming the drug resistance of the existing drugs remains a technical problem to be solved in the art. Disclosure of Invention In order to overcome the defects of the prior art, the application provides a treatment method for targeted KRAS mutant pancreatic duct adenocarcinoma, so as to supplement the defects of a clinical KRAS mutant treatment scheme. The compound provided by the embodiment of the invention has a structure shown in the following formula (I), or pharmaceutically acceptable salt thereof: the compound of formula (I), Wherein R 1 is H or C 1-C4 alkyl, R 2 is cyclohexyl or its substituent. The present application provides the use of a compound of formula (I) ab