Active composition for treating prostatic cancer, medicine and application

Abstract

The invention belongs to the field of medicine treatment, and particularly relates to an active composition for treating prostatic cancer, which comprises an active component A and an active component B, wherein the active component A is a compound with a structure shown in a formula 1 and a pharmaceutically acceptable derivative thereof; and the active component B is a compound with a structure shown in a formula 2 and a pharmaceutically acceptable derivative thereof. According to the invention, the formula 1 and the formula 2 are innovatively combined for use, so that synergy can be accidentally realized, and the treatment effect on prostatic cancer can be remarkably improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to pharmaceuticals for the treatment of prostate cancer. Background Technology

[0002] Prostate cancer development and progression depend on androgens; therefore, androgen deprivation therapy (ADT) is one of the most important treatment options for prostate cancer. Some prostate cancer patients who receive ADT gradually develop tolerance, and the disease progresses to castration-resistant prostate cancer (CRPC), severely impacting patient prognosis. Studies have found that the most common recurrence-related gene alteration in CRPC tumor tissue is mutation or amplification of the androgen receptor (AR), accounting for 62.7% of all gene alterations. Novel endocrine therapy drugs are a series of small molecule compounds developed targeting the AR signaling axis, mainly divided into two categories: the first category consists of inhibitors developed targeting key enzymes in the androgen synthesis pathway (such as 17α-hydroxylase), with abiraterone as a representative drug; the second category consists of novel AR receptor antagonists developed targeting androgen receptor proteins, with enzalutamide as a representative drug.

[0003] Clinical studies have found that novel endocrine therapy drugs can improve the survival of most CRPC patients, but all patients experience a decrease in drug sensitivity within 24 months of treatment. Therefore, elucidating the molecular mechanisms regulating the sensitivity of CRPC to novel endocrine therapy drugs, thereby improving the therapeutic effect of these drugs, remains a challenge in current prostate cancer research.

[0004] To address the problems with existing drugs, some combination drug solutions have also been proposed in the prior art. For example, patent document with publication number AU2025210784A1 discloses a combination of tapolaparib and an anti-androgen for the treatment of metastatic castration-sensitive prostate cancer with DDR gene mutations.

[0005] Patent document with publication number MX2025003936A discloses a combination pharmaceutical preparation comprising a combination of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof.

[0006] In summary, although there are some combination therapy options available in the current technology, these options need to be further expanded, and the drug sensitivity activity of the compositions needs to be further improved. Summary of the Invention

[0007] To address the problem of insufficient drug sensitivity synergy in existing active ingredients for treating prostate cancer, the primary objective of this invention is to provide an active composition for treating prostate cancer, aiming to improve the therapeutic effect of prostate cancer based on the combined synergy of the components.

[0008] A second objective of this invention is to provide the application of the aforementioned active composition for treating prostate cancer.

[0009] The present invention also provides a medicament for treating prostate cancer comprising the said active ingredient.

[0010] An active composition for treating prostate cancer, comprising active ingredient A and active ingredient B;

[0011] Among them, active ingredient A is a compound with the structure of Formula 1 and its pharmaceutically acceptable derivatives;

[0012] Active ingredient B is a compound of formula 2 and its pharmaceutically acceptable derivatives;

[0013] Formula 1

[0014] Formula 2

[0015] R1 is H, C2~C 12 Alkyl or C2~C 12 alkoxy groups;

[0016] R2 to R4 are individually C1 to C3 alkyl groups.

[0017] This invention innovatively combines Formula 1 and Formula 2, which unexpectedly achieves a synergistic effect and can significantly improve the treatment effect of prostate cancer.

[0018] In this invention, active ingredient A is a compound of formula 1A and its pharmaceutically acceptable derivatives;

[0019] Formula 1A

[0020] In Formula 1A, R1 is a C6-C8 alkyl group.

[0021] In this invention, the active ingredient B is Formula 2A and its pharmaceutically acceptable derivatives;

[0022]

[0023] Equation 2A.

[0024] In this invention, the weight ratio of active ingredient A to active ingredient B is 1:0.5~2; more specifically, it can be 1:0.9~1.1.

[0025] The present invention also provides an application of the active composition for treating prostate cancer, using it as an active ingredient in the preparation of a drug for treating prostate cancer.

[0026] The application described in this invention combines the active ingredient with pharmaceutically acceptable excipients to prepare a pharmaceutically acceptable medicament for the treatment of prostate cancer.

[0027] The present invention also provides a medicament for treating prostate cancer, comprising a pharmaceutically effective amount of the said active composition for treating prostate cancer.

[0028] In this invention, the drug for treating prostate cancer further comprises pharmaceutically acceptable excipients.

[0029] The drug for treating prostate cancer described in this invention has a pharmaceutically acceptable dosage form.

[0030] The drug for treating prostate cancer described in this invention is in the form of an oral preparation or an injectable preparation.

[0031] Beneficial effects

[0032] The present invention demonstrates that the combined use of Formula 1 and Formula 2 can achieve synergy, obtain good therapeutic sensitization effect, and significantly improve the treatment effect of prostate cancer. Attached Figure Description

[0033] Figure 1 The experimental results of combining Formula A and Formula 2 to treat prostate cancer with good results are shown in the figure. Detailed Implementation

[0034] In this invention, Formula 1 is typically implemented using Formula A:

[0035] Formula A

[0036] In the following specific embodiments, unless otherwise stated, Formula 2 refers to Formula 2A.

[0037] (1) Cell lines and cell culture

[0038] This protocol utilized human prostate cancer cell lines C4-2 and 22Rv1. All cell lines were supplied by Pronosei Life Sciences & Technology Co., Ltd. (China) and underwent rigorous short tandem repeat (STR) analysis to ensure their authenticity. Cells were cultured in a humidified incubator at 37°C and 5% CO2. C4-2 and 22Rv1 cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. All media and serum were purchased from Gibco (DMEM: #11320033, RPMI 1640: #11875093, serum: #A5256701, USA), while penicillin-streptomycin was purchased from Thermo Fisher Scientific (#15140122, USA). C4-2 and 22Rv1 cells were seeded in 6-well plates and treated with the drug when cell confluence reached 70%-80%.

[0039] (2) Construction of drug-resistant cell lines according to Formula 2

[0040] Core cycle: Each cycle lasts 2 weeks, with medication added in week 1 and discontinued in week 2. This cycle is repeated 6 times (a total of 12 weeks, approximately 3 months).

[0041] Specific steps:

[0042] Week 1 - Dosage Addition Week

[0043] Seed 22RV1 or C4-2 cells (2 × 10⁻⁶) 5 / well). After the cells adhere, replace the medium with 10 μM Formula 2. Replace the medium with fresh drug-containing medium once midway through the drug administration cycle to maintain drug concentration and nutrients.

[0044] Week 2 - Medication Discontinuation Week

[0045] Remove the drug-containing medium and gently wash the cells 1-2 times with PBS to remove as much drug as possible. Replace with complete medium without Formula 2. If cell density is high during this period, digestion and passage can be performed to maintain optimal growth. Use normal medium. Use the same Formula 2 concentration (10 μM) throughout the entire 3-month period. Finally, obtain Formula 2-resistant C4-2 or 22Rv1 cells (C4-2 R and 22Rv1 R) for further validation.

[0046] (3) Drug intervention

[0047] Dissolve the dry powders of Formula A and Formula 2 in DMSO to prepare a 10 mM stock solution. Add Formula A or Formula 2 to a 6-well plate inoculated with prostate cancer cells. For example, using a culture system of 2 ml RPMI 1640 complete medium per well and a treatment concentration of 10 μM for Formula A, 2 μl of the 10 mM stock solution should be added. Incubate for 24 hours, then assess cell proliferation using a CCK-8 assay.

[0048] (4) Cell proliferation capacity detection - CCK-8 assay

[0049] We used a CCK-8 assay kit (#C0037, Beyotime, China) for CCK-8 detection. Cells were collected from different treatment groups, thoroughly resuspended in culture medium, and counted. The cell suspension was then diluted to ensure 5000 cells per well (100 μl, adjusted according to cell viability) in each 96-well plate. Each group contained at least three replicates. Wells containing only culture medium (without cells) were reserved as blank controls. CCK-8 solution was added to each well and incubated in a constant temperature incubator for 1 hour. Care was taken to avoid air bubbles in the wells, as this would affect the OD reading. The absorbance of each well was then measured using a microplate reader at a wavelength of 450 nm, and the IC50 value was calculated.

[0050] (5) Subcutaneous tumor formation in nude mice

[0051] All animal experiments were approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (No. 20241019). Six-week-old male nude mice were obtained from Hunan Silek Jingda Laboratory Animal Co., Ltd. These mice were housed in a specific pathogen-free (SPF) animal facility. All animals were randomly assigned to different groups. 22Rv1 cells were injected subcutaneously into the right buttock of each mouse at a rate of 5 million per mouse. Tumors were allowed to grow to 50 mm. 3 At that time, the tumor volume was measured every other day (volume = length × width). 2 / 2), and administered drugs in the following groups: Group A: Formula 2 monotherapy (10 mg / kg), Group B: Formula A monotherapy (10 mg / kg), Group C: Formula 2 (5 mg / kg) combined with Formula A (5 mg / kg). The tumor volume in the control group was increased to 1000 mm. 3 The experiment was terminated at the appropriate time, and the subcutaneous tumor was removed, weighed, and photographed.

[0052] (6) Experimental results

[0053] Figure 1Cells A and B, C4-2 (A) or 22RV1 (B) were treated for 24 hours with or without Formula A (10 μM), Formula 2 (10 μM) alone, or Formula A (5 μM) combined with Formula B (5 μM), and then treated with different concentrations of enzalutamide for 24 hours. CCK-8 assays were performed to assess cell proliferation in each group. Both Formula A and Formula 2 alone inhibited cell proliferation, with the combined use of Formula A and Formula 2 showing a more significant inhibitory effect.

[0054] Figure 1 C and D, C4-2 (C) or 22RV1 (D) cells were treated with or without Formula A (10 μM) and simultaneously treated with a series of concentration gradients of Formula 2 for 24 hours, followed by CCK-8 assay. The results indicated that Formula A reduced the IC50 value of Formula 2 in prostate cancer cells, suggesting that Formula A increased the sensitivity of prostate cancer cells to Formula 2.

[0055] Figure 1 In E and F, C4-2 R(E) and 22Rv1 R(F) cells resistant to Formula 2 were treated with or without Formula A (10 μM) while simultaneously treated with a series of concentration gradients of Formula 2 for 24 hours, followed by CCK-8 assay. The results indicated that Formula A reduced the IC50 value of Formula 2 in prostate cancer cells, suggesting that Formula A reversed the treatment resistance of Formula 2 in Formula 2-resistant cells.

[0056] Figure 1 .GI, subcutaneous tumorigenesis experiments in nude mice showed that treatment with either Formula A or Formula 2 alone inhibited tumor growth, with the combination of Formula A and Formula 2 showing a more significant inhibitory effect. Tumor images (G), growth curves (H), and tumor mass (I) are shown in the figures. Data represent mean ± standard deviation (n = 5). p < 0.01; p < 0.001.

[0057] In summary, the combined use of Formula 1 and Formula 2 can achieve synergy, obtain good therapeutic sensitization effect, and significantly improve the treatment effect of prostate cancer.

Claims

1. An active composition for treating prostate cancer, characterized in that, It contains active ingredient A and active ingredient B; Among them, active ingredient A is a compound with the structure of Formula 1 and its pharmaceutically acceptable derivatives; Active ingredient B is a compound of formula 2 and its pharmaceutically acceptable derivatives; Formula 1 Formula 2 R1 is H, C2~C 12 Alkyl or C2~C 12 alkoxy groups; R2 to R4 are individually C1 to C3 alkyl groups.

2. The active composition for treating prostate cancer as described in claim 1, characterized in that, Active ingredient A is a compound of formula 1A and its pharmaceutically acceptable derivatives; Formula 1A In Formula 1A, R1 is a C6-C8 alkyl group.

3. The active composition for treating prostate cancer as described in claim 1, characterized in that, The active ingredient B is of formula 2A and its pharmaceutically acceptable derivatives; ； Equation 2A.

4. The active composition for treating prostate cancer according to any one of claims 1 to 3, characterized in that, The weight ratio of active ingredient A to active ingredient B is 1:0.5~2.

5. The use of the active composition for treating prostate cancer according to any one of claims 1 to 4, characterized in that, It is used as an active ingredient in the preparation of drugs for treating prostate cancer.

6. The application of the active composition for treating prostate cancer as described in claim 5, characterized in that, The active ingredient is combined with pharmaceutically acceptable excipients to prepare a pharmaceutically acceptable medicament for the treatment of prostate cancer.

7. A drug for treating prostate cancer, characterized in that, The active composition for treating prostate cancer according to any one of claims 1 to 4 contains a pharmaceutically effective amount.

8. The medicament for treating prostate cancer as described in claim 7, characterized in that, It also contains pharmaceutically acceptable excipients.

9. The medicament for treating prostate cancer as described in claim 8, characterized in that, It has a pharmaceutically acceptable dosage form.

10. The medicament for treating prostate cancer as described in claim 9, characterized in that, The dosage form is an oral preparation or an injectable preparation.

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