Use of STK31 kinase inhibitor ciclopirox compounds for treatment of pancreatic ductal adenocarcinoma

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a ciclopirox compound in a medicine for treating cancers induced by KRAS G12D mutation, and 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 therapy advantages. Animal experiment results show that the ciclopirox compound provided by the invention can effectively inhibit tumor growth and down-regulate phosphorylated STK31 protein expression. The composition is clear in component and simple and convenient to prepare, and provides a new strategy for overcoming the drug resistance of pancreatic cancer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel use of STK31 kinase inhibitor ciclopirox ketone compounds in the treatment of pancreatic ductal adenocarcinoma. Background Technology

[0002] Pancreatic cancer is one of the most common malignant tumors of the digestive system, characterized by its insidious onset, high malignancy, and extremely poor prognosis. Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas, with a 5-year survival rate of less than 10%. Studies report that 100,000 new cases of pancreatic ductal adenocarcinoma are diagnosed in my country each year. Currently, treatment methods for pancreatic ductal adenocarcinoma mainly include surgery (such as pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy), chemotherapy (such as FOLFIRONOX and mFOLFIRINOX), radiotherapy, interventional therapy (such as transarterial chemotherapy, ablation therapy, PTCD, and biliary stent implantation), and supportive care. Pancreatic ductal adenocarcinoma is a "cold tumor," characterized by its immunosuppressive microenvironment, low immunogenicity, and dense matrix, resulting in a generally poor response to traditional immune checkpoint inhibitors (such as anti-PD-1 / PD-L1 or CTLA-4 inhibitors). Currently, no single treatment method can effectively improve the survival rate of patients with pancreatic ductal adenocarcinoma.

[0003] For patients with advanced pancreatic cancer, chemotherapy remains the primary treatment. Gemcitabine is a first-line drug for treating pancreatic cancer, but resistance is widespread, with over 80% of PDAC patients exhibiting resistance. Currently, many anti-tumor drug development and treatment strategies target the abnormal phosphorylation process.

[0004] In 1982, HRAS and KRAS, members of the RAS gene family, were discovered, becoming the first human cancer genes. KRAS was later identified as one of the most frequently mutated oncogenes. Among all RAS genes, KRAS is the most frequently mutated, accounting for approximately 80% of all RAS mutations. Notably, RAS mutations exhibit significant tissue specificity; the most common and deadliest cancer types, such as colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC), are all closely associated with KRAS mutations (43%, 90%, and 31%, respectively). However, it took nearly 40 years to develop clinically effective inhibitors for RAS-mutated cancers. In 2013, Shokat and colleagues discovered a druggable pocket in KRAS, laying a solid foundation for subsequent drug development. Currently, drugs targeting KRAS gene mutations primarily target KRAS G12C (glycine mutated to cysteine) and act as inhibitors to exert their therapeutic effects. It is noteworthy that in PDAC, KRAS G12D (51%) and KRASG12V (30%) are the more common mutation types, while KRAS G12C occurs in only 2%. Although both KRAS G12D and KRASG12C mutations occur at amino acid 12, they differ significantly in structure, molecular mechanism, tumor biology characteristics, and response to KRAS inhibitors.

[0005] Patients with KRAS G12D-mutant PDAC have a worse prognosis than those with other mutations, specifically manifested in shorter survival, increased tumor invasiveness, poor response to conventional chemotherapy, and a higher risk of postoperative recurrence. In KRAS G12D, the amino acid at position 12 changes from glycine to aspartic acid, with a negatively charged carboxyl group (-COOH) as its side chain. This group lacks the nucleophilic nature of the cysteine ​​thiol group and therefore cannot form a stable covalent bond. Consequently, G12D-mutant KRAS is generally insensitive to KRAS G12C-specific inhibitors. More regrettably, these novel KRAS inhibitors have been reported to potentially lead to new KRAS mutations (such as KRAS Y96D / NRASQ61L / NRAS Q61R) in patients with lung and colorectal cancer, activating multiple downstream signaling pathways and even altering the pathological type of tissues, thereby resulting in acquired resistance.

[0006] Therefore, developing new solutions that can effectively inhibit the KRAS signaling pathway and overcome existing drug resistance remains a pressing technical challenge in this field. Summary of the Invention

[0007] To overcome the shortcomings of existing technologies, this application provides a treatment method for targeted KRAS-mutant pancreatic ductal adenocarcinoma, supplementing the deficiencies of clinical KRAS-mutant treatment regimens.

[0008] The compounds provided in the embodiments of the present invention have the structure shown in formula (I), or a pharmaceutically acceptable salt thereof: Formula (I), Where R 1 For H or C1-C4 alkyl groups: R 2 It is cyclohexyl or its substitutes.

[0009] This application provides the use of the compound represented by formula (I) above for the preparation of a medicament for treating cancers induced by KRAS G12D mutations, including pancreatic ductal adenocarcinoma and colorectal cancer.

[0010] Preferably, the pancreatic cancer is a KRAS G12D mutant pancreatic ductal adenocarcinoma.

[0011] Preferably, the compound exerts its pharmacological activity by downregulating the expression of phosphorylated STK31 protein to inhibit the activity of KRAS G12D mutant pancreatic ductal adenocarcinoma cells.

[0012] Preferably, the amount of the compound used is 30 mg / kg ± 10%.

[0013] The beneficial technical effects of this invention are as follows: The ciclopirox ketone compound of this invention significantly inhibits the activity of KRAS G12D mutant pancreatic cancer cells, while exhibiting weaker inhibition against wild-type cells, demonstrating potential advantages for targeted therapy. Animal experiments show that the ciclopirox ketone compound of this invention can effectively inhibit tumor growth and downregulate the expression of phosphorylated STK31 protein. This invention has clearly defined components and is easy to prepare, providing a new strategy for overcoming drug resistance in pancreatic cancer. Attached Figure Description

[0014] Figure 1 A schematic diagram of the workflow for screening esiRNA libraries in KRAS-mutant and KRAS-wild-type pancreatic cancer cell lines; Figure 2 The image shows the detection results of STK31 expression in pancreatic cancer KRAS-mutant cells and tissues, and the relationship between STK31 expression and the prognosis of PDAC patients. Figure 3 Overexpression of STK31 domains in KRAS wild-type BXPC3 cells showed that the STK31 kinase domain promotes tumor cell invasion.

[0015] Figure 4 Flowchart for screening STK31 small molecule inhibitors; Figure 5 A 2D structural simulation of the STK31 kinase domain bound to ciclopirox ketone; Figure 6 A 3D simulation diagram of the binding of the STK31 kinase domain to ciclopirox ketone; Figure 7 The results show the affinity constants of STK31 protein and ciclopirox ketone in the SPR experiment. Figures 8-9 The results of IC50 assays for ciclopirox ketone on KRAS G12D mutant PDAC cell lines Panc-1 and CFPAC-1, KRAS wild-type cell line BxPC3, and colorectal cancer KRAS wild-type cell lines HT29 and RKO. Figure 10 and Figure 11 The results show the effects of ciclopirox ketone, gemcitabine, and the combination of ciclopirox ketone and gemcitabine on cell growth and apoptosis in KRAS mutant and KRAS wild-type PDAC cells. Figure 12 The results of subcutaneous tumorigenic mice treated with ciclopirox olamine and gemcitabine. Detailed Implementation

[0016] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0017] Unless otherwise specified in the examples, the conditions were performed according to standard conditions or the manufacturer's recommendations. All reagents and instruments used were commercially available products unless otherwise specified.

[0018] In this application, the term "pharmaceutically acceptable" generally refers to one or more non-toxic substances that do not interfere with the effectiveness of the biological activity of the active ingredient. Such formulations may typically contain salts, excipients, buffers, preservatives, compatibility carriers, and optionally other therapeutic agents. When used in medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts, and these should not be excluded from the scope of this application. Such pharmacologically and pharmaceutically acceptable salts include salts prepared from acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, citric acid, boric acid, formic acid, malonic acid, and succinic acid. Pharmaceutically acceptable salts may also be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts.

[0019] Ciclopirox olamine is known as an antifungal drug and has been shown in recent years to have good antitumor activity against hematologic malignancies and solid tumors, making it a promising alternative to gemcitabine for the treatment of pancreatic cancer. However, ciclopirox olamine monotherapy also has the problem of easily inducing drug resistance, and its efficacy still needs further improvement.

[0020] The inventors conducted high-throughput screening of an esiRNA library (Endoribonuclease-prepared siRNAs, covering 634 human kinases) on the KRAS mutant PDAC cell line SW1990 and the KRAS wild-type PDAC cell line BxPC3. They discovered that siRNAs targeting serine / threonine kinase 31 (STK31) showed the best inhibitory effect on the growth of KRAS mutant PDAC cells without affecting the growth of KRAS wild-type PDAC cells. The screening process and corresponding data are detailed in [link to relevant documentation]. Figure 1 , Figure 1 This study demonstrated that knocking down STK31 can reduce the growth and proliferation of KRAS-mutant pancreatic cancer cell lines.

[0021] Further research revealed that STK31 is highly expressed in the tissues and cells of KRAS-mutant PDAC, and the expression level of STK31 is associated with the prognosis of pancreatic cancer patients. See the experimental results below. Figure 2 STK31 is regulated by the KRAS protein and can therefore be considered an important downstream kinase controlling the growth of KRAS-mutant PDAC cells, making it an ideal drug target. The inventors discovered that the kinase region of STK31 promotes the growth and proliferation of PDAC tumor cells; experimental results are shown below. Figure 3 .

[0022] By Alphafold 3 fitting of the kinase domain of STK31 and screening of a drug library, the inventors discovered that ciclopirox ketone binds to the kinase domain of STK31. Figure 4-5 It has an inhibitory effect on the growth of PDAC cell lines and is highly sensitive to KRAS mutant cell lines, providing a new strategy for overcoming drug resistance in pancreatic cancer. Figures 8-12 ).

[0023] This invention provides the use of the STK31 kinase inhibitor ciclopirox ketone compound for the treatment of KRAS G12D mutation-related cancers. Further, the cancers include pancreatic ductal adenocarcinoma and colorectal cancer, and the compound has the structure shown in formula (I) below, or a pharmaceutically acceptable salt thereof: Formula (I), Where R 1 H, C1-C4 alkyl group: R2 It is cyclohexyl or its substitutes.

[0024] Furthermore, the compound shown in formula (I) has an (R)-configuration or an (S)-configuration.

[0025] The inventors discovered through screening that STK31 is a downstream kinase controlling cell growth in KRAS mutations. Using Alphafold3 artificial intelligence, they established a model of the kinase domain (710-1019aa) of STK31 and conducted molecular docking and experimental verification screening with small molecule inhibitors from various compound libraries. They found that ciclopirox ketone can effectively target the kinase domain of STK31, and experimentally demonstrated that ciclopirox ketone can target STK31 and has a good therapeutic effect on cancers such as pancreatic cancer with KRAS G12D mutations.

[0026] Currently, inhibitors targeting KRAS mutations primarily target G12C. Selective inhibitors targeting KRAS G12D (mutated to aspartic acid) are still relatively few, even though this mutation accounts for approximately 28% of all KRAS mutations and is the most common mutation in CRC and PDAC. KRAS G12D inhibitors, such as JAB-22000, UA022, and BPI-501836, are reportedly in preclinical research. Experiments have also shown that in a KRAS G12D-mutant PDAC mouse model, MRTX1133 alone or the standard treatment gemcitabine only inhibits tumor metastasis for up to two weeks, while the combination of both can lead to long-term tumor regression. However, whether acquired resistance develops later remains unknown.

[0027] Current experimental data indicates that KRAS G12C inhibitors are not effective against KRAS G12D; for example, sotorasirb explicitly states in its product information that it is ineffective against the G12D target. In the treatment of pancreatic ductal adenocarcinoma (PDAC), gemcitabine is the primary chemotherapy drug, but resistance is widespread, with over 80% of PDAC patients exhibiting resistance. Currently, many anti-tumor drug development and treatment strategies target the inhibition of abnormal phosphorylation processes.

[0028] The inventors of this application discovered in experiments that STK31 is a novel target for PDAC, specific for KRAS mutants, and that STK31 promotes PDAC progression in dependence of its phosphokinase activity. Therefore, the inventors developed a small molecule inhibitor targeting the kinase domain of STK31.

[0029] The inventors used AlphaFold3 to model the molecular structure of STK31 (see process and related data). Figure 4Furthermore, using molecular docking methods, we focused on screening drugs targeting the kinase domains (710-1019aa) of STK31 (see schematic diagram of the domains). Figure 5 The STK31 key site mainly consists of amino acids TYR-103, ASP-163, LYS-49, PRO-104, PHE-152, LEU-30, LEU-36, LEU-47, TYR-102, ASN-107, and ARG-105 (see structural diagram). Figure 6 ).

[0030] During the drug screening process, the inventors used multiple compound libraries. After initial screening, they discovered that ciclopirox could bind to the kinase domain of STK31. It was predicted that the NH2 side chain of arginine (Arg34) in STK31 would form a hydrogen bond with the oxacyclooxygen atom in the ciclopirox molecule (see...). Figure 6 Furthermore, hydrophobic residues such as leucine (Leu36, Leu47, Leu30) and phenylalanine (Phe152) surround the hydrophobic region of ciclopirox ketone, forming a hydrophobic encapsulation structure, thereby enhancing the intermolecular binding stability. Through surface plasmon resonance (SPR) experiments, the inventors discovered that STK31 on the CM5 chip can bind to ciclopirox ketone with an affinity constant of 3.81 μM (see...). Figure 7 This indicates that ciclopirox ketone has a strong affinity for STK31 protein.

[0031] Through CCK8, IC 50 Through experiments, the inventors discovered that ciclopirox ketone, represented by formula (I), has an inhibitory effect on the growth of pancreatic ductal adenocarcinoma cell lines.

[0032] In addition, treatment of the Panc-1 cell line with ciclopirox ketone significantly inhibited the activity of phosphorylation sites at STK31-T776 and Y992 (see [link]). Figure 12 In animal experiments, a subcutaneous tumor model of Panc-1 cells in nude mice was created by treating the cells with ciclopirox olfaction (30 mg / kg). The results demonstrated that ciclopirox olfaction inhibited tumor size in the nude mice. Western blotting of tumor tissue revealed that phosphorylation of STK31 protein was inhibited, while total protein levels showed no significant inhibition. Furthermore, the drug also includes at least one of an excipient, a buffer, and a compatibility carrier; and preferably, the compatibility carrier is microcrystalline cellulose, lactose, or polyethylene glycol.

[0033] Furthermore, the drug also contains a second active ingredient selected from at least one of immune checkpoint inhibitors, chemotherapeutic agents, and anti-inflammatory agents.

[0034] Furthermore, the dosage form of the drug may be tablets, capsules, injections, or inhalation formulations.

[0035] Furthermore, the drug is administered orally or intravenously.

[0036] The present invention will be described in detail below through specific embodiments. Example 1

[0037] This embodiment provides a ciclopirox ketone compound of formula (I) for treating pancreatic cancer, or a pharmaceutically acceptable salt thereof: Formula (I), Where R 1 For H; R 2 It is a cyclohexyl group.

[0038] 1.1 Cells and Culture Methods Panc-1 (KRAS) human pancreatic cancer cells G12D Mutant type), colorectal cancer cells HT29 (KRAS wild type, KRAS) WT ) and RKO (KRAS WT Human pancreatic cancer cells CFPAC-1 (KRAS) were cultured in DMEM medium. G12V (mutant type) and BxPC3 (KRAS) WT Cells were cultured using RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin, and cultured at 37°C and 5% CO2. Cells were passaged when the confluence reached approximately 90%.

[0039] 1.2 CCK-8 Experiment Select Panc-1 (KRAS) in the logarithmic growth phase. G12D CFPAC-1 (KRAS) G12V BxPC3 (KRAS) WT ), HT29 (KRAS) WT ) and RKO (KRAS WT Cells were digested with trypsin and then prepared into single-cell suspensions using appropriate culture media, with cell density adjusted to 5 × 10⁻⁶ cells / cells. 4Cells were seeded at a rate of 100 μL / well into 96-well plates to achieve a cell count of 5000 per well, and incubated for 24 h. The ciclopirox ol compound was prepared as a 100 mM stock solution using DMSO, and then serially diluted with DMEM medium to prepare working solutions with final concentrations of 0, 2.5, 5, 10, 20, 40, 80, 160, and 320 μM, ensuring that the final DMSO concentration in all working solutions was consistent and did not exceed 0.5%. After cell attachment, the original culture medium was discarded, and 100 μL of different concentrations of the working solution was added to each well. A blank group (containing only culture medium and an equal volume of DMSO, without cells) and a control group (containing culture medium, cells, and an equal volume of DMSO) were also established, with three replicates in each group. After culturing for another 48 hours, the 96-well plate was removed, and 10 μL of LCK-8 reagent was added to each well in the dark, avoiding the formation of air bubbles. After incubation for 1 hour, the absorbance (OD value) of each well at 450 nm was measured using a microplate reader. The average value of each group was taken, and the cell inhibition rate at each concentration was calculated: Inhibition rate = [1 - (OD of each experimental group - OD of the blank group) / (OD of the control group - OD of the blank group)] × 100%. Finally, the half-maximal inhibitory concentration (IC50) of the drug for the growth of pancreatic cancer cells was calculated using software. 50 The specific results are shown in Table 1.

[0040] Table 1 As shown in Table 1, the ciclopirox olamine of Example 1 of this invention has an inhibitory effect on the growth of pancreatic ductal adenocarcinoma cell lines, and is more sensitive to Panc-1 (KRAS G12D) cells than to BxPC3 (KRAS wild-type) cells. Meanwhile, this experiment introduced KRAS wild-type colorectal cancer cell lines for comparison. The results showed that the ciclopirox olamine compound of Example 1 was not sensitive to any KRAS wild-type colorectal cancer cell lines, and the IC50 values ​​for HT29 (KRAS wild-type) and RKO (KRAS wild-type) were [not specified]. 50 The higher value indicates that the ciclopirox ketone compound of the present invention has better specificity for KRAS mutant cells than for KRAS wild-type cell lines.

[0041] Figure 8 and Figure 9 The graph shows the results of this embodiment. It can be seen from the graph that ciclopirox ketone is more sensitive to Panc-1 (KRASG12D) cells than to BxPC3 (KRAS wild-type) cells, with an IC50 value of [missing value]. 50 A 7-fold difference (Panc-1 ciclopirox ketone IC) 50 3.319 μM; BxPC3 ciclopirox olamine IC 50 :22 μM).

[0042] Therefore, at a drug concentration of 3 μM, ciclopirox ketone showed significant killing effect on the KRAS-mutant Panc-1 and CFPAC-1 cell lines, but no significant effect on the KRAS wild-type BxPC3 cell line. This indicates that the ciclopirox ketone compound can specifically target the mutations induced by KRAS mutations.

[0043] The inventors introduced KRAS wild-type cell lines of colorectal cancer for comparison and also observed that the ciclopirox ketone compound was insensitive to KRAS wild-type cell lines (see...). Figure 9 ), in the KRAS wild-type cell line HT29 (IC) for colorectal cancer 50 IC50 in the RKO cell line (32 μM) and (150.4 μM) 50 The results showed that the ciclopirox ketone compound was more specific to KRAS mutant cells than to KRAS wild-type cell lines. Example 2

[0044] Panc-1 (KRAS G12D), CFPAC-1 (KRAS G12V), and BxPC3 (KRAS wild-type) cells in logarithmic growth phase were selected, digested with trypsin, and then prepared into single-cell suspensions in their respective culture media. The cell densities were adjusted to 4 × 10⁻⁶ cells / cells. 4 Cells were seeded at a rate of 100 μL / well in 96-well plates to achieve a cell count of 4000 cells per well, and incubated for 24 h. A 100 mM stock solution of ciclopirox ol was prepared using DMSO, then diluted with DMEM to prepare a 3 μM working solution. A control solution containing only DMSO was also prepared. After cell attachment, the original culture medium was discarded, and 100 μL of the corresponding working solution was added to each well (for the solvent control group (DMSO), one 3 μM test group (ciclopirox ol), and one 3 μM control group (gemcitabine)). A combination of 3 μM ciclopirox ol + 1 μM gemcitabine was also added, with three replicates per group. Cell proliferation was measured at five time points: 0, 1, 3, 5, and 7 days. Every 48 h, all wells were replaced with fresh working solution or solvent control medium. On days 0, 1, 3, 5, and 7 after culture, the corresponding 96-well plates were removed, and 10 μL of CCK-8 reagent was added to each well, avoiding the formation of air bubbles. After incubation in the dark for 4 h, the absorbance (OD value) of each well was measured using a microplate reader at a wavelength of 450 nm. After all time points were measured, a cell growth curve was plotted with culture time on the x-axis and OD value on the y-axis.

[0045] See results Figure 10In experiment A-10C, results showed that in the KRAS-mutant PDAC cell lines CFPAC-1 and Panc-1, ciclopirox ol alone was more effective at killing tumor cells than gemcitabine alone, and also more effective than the combination of ciclopirox ol and gemcitabine. Conversely, in the KRAS wild-type PDAC cell line BxPC3, ciclopirox ol alone was less effective than gemcitabine alone, and the combination of ciclopirox ol and gemcitabine was less effective than gemcitabine monotherapy. These results indicate that KRAS-mutant PDAC cell lines are more sensitive to ciclopirox ol, but its combination with gemcitabine did not show a synergistic effect, and ciclopirox ol has no side effects on wild-type PDAC cell lines. Figure 11 As shown in A-11C, ciclopirox ketone treatment significantly induced apoptosis in KRAS mutant Panc-1 and CFPAC-1 cells; however, no obvious apoptosis was observed in the KRAS wild-type cell line BxPC3. Example 3

[0046] 2.1 Cells and culture methods: Same as in Example 1 2.2 Laboratory Animals Twenty healthy female BALB / c-nu nude mice (18-20 g) were used. Before the experiment, the mice were acclimatized for 3 days in a sterile and ventilated environment (temperature 25±2℃, relative humidity 50±10%, day-night cycle: 12h).

[0047] 2.3 Tumor formation experiment in nude mice Take the logarithmic growth phase of Panc-1 (KRAS) G12D Cell suspension (1×10) 7 0.2 mL of the inoculum (per tumor cell / mL) was injected into the right rump of BALB / c-nu nude mice. After excluding mice that failed to develop tumors, the tumors in the remaining nude mice were inoculated until the average tumor volume reached 100 mm². 3 In the above experiment, 15 tumor-bearing nude mice were randomly divided into 3 groups (n=5) according to tumor volume: model group (equal volume of physiological saline), ciclopirox olamine group (15 mg / kg based on total compound mass), and gemcitabine group (15 mg / kg based on total compound mass). Each group received intraperitoneal injection once daily for 28 consecutive days. The mice were sacrificed 24 hours after the last administration, and tumor tissue was collected for volume determination. Western blot analysis was used to detect the phosphorylation expression of STK31 protein in the tumor tissue. The experimental results are shown below. Figure 11 A-11C.

[0048] Figure 12 A and Figure 12Figure B shows the tumor suppression in mice. As can be seen from the figure, both ciclopirox olamine and gemcitabine significantly reduced the size of the tumor; and ciclopirox olamine was slightly more effective than gemcitabine. Figure 12 The results showed that 30 mg / kg of ciclopirox olamine compound could significantly inhibit the growth and proliferation marker Ki67 in tumor cells.

[0049] Figure 12 The results from D-12F showed that ciclopirox ketone compounds could successfully inhibit the phosphorylation expression of STK31 protein.

[0050] The inventors also tested other structures shown in formula (I), and the results were similar to those of the above embodiments.

[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancers induced by KRAS G12D mutations. Formula (I), Where R 1 H, C1-C4 alkyl group: R 2 It is cyclohexyl or its substitutes. The cancers mentioned include pancreatic ductal adenocarcinoma and colorectal cancer.

2. The use according to claim 1, characterized in that, The pancreatic cancer in question is a KRAS G12D mutant pancreatic ductal adenocarcinoma.

3. The use according to claim 1, characterized in that, The compound exerts its drug activity by downregulating the expression of phosphorylated STK31 protein to inhibit the activity of KRAS G12D mutant pancreatic ductal adenocarcinoma cells.

4. The use according to claim 1, characterized in that, The amount of the compound used is 30 mg / kg ± 10%.

5. The use according to any one of claims 1-4, characterized in that, The drug also includes at least one of excipients, buffers, and compatible carriers.

6. The use according to any one of claims 1-4, characterized in that, The compound shown in formula (I) has either (R)-configuration or (S)-configuration.

7. The use according to any one of claims 1-4, characterized in that, The drug also contains a second active ingredient selected from at least one of immune checkpoint inhibitors, chemotherapeutic agents, and anti-inflammatory agents.

8. The use according to any one of claims 1-4, characterized in that, The dosage form of the drug is tablets, capsules, injections, or inhalation preparations.

9. The use according to claim 5, characterized in that, The compatibility carrier is microcrystalline cellulose, lactose, or polyethylene glycol.

10. The use according to any one of claims 1-4, characterized in that, The drug can be administered orally or intravenously.

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