A combination of a glucokinase activator and a pi3k inhibitor

Abstract

The present application relates to a kind of combination of glucose kinase activator and PI3K inhibitor.The present application finds that glucose kinase activator can not only alleviate the hyperglycemia caused by PI3K inhibitor, but also can enhance the anti-tumor effect of PI3K inhibitor, and promote the further clinical application of PI3K inhibitor.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of cancer treatment, and particularly relates to a combination of a glucokinase activator and a PI3K inhibitor. BACKGROUND

[0002] In peripheral tissues, PI3K inhibitors have become a viable target for novel anticancer therapies. Successful drug design has resulted in three classes of potent and selective small molecule inhibitors that have progressed from late preclinical testing to different stages of clinical development. In the past few years, several classes of potent and selective small molecule PI3K inhibitors have been developed, and at least fifteen compounds have been advanced into clinical trials as new anticancer drugs (Akinleye et al., Journal of Hematology & Oncology, 6:88, 2013).

[0003] However, the common adverse effect of hyperglycemia poses a major challenge to the clinical application of PI3K inhibitors. There is an urgent need to find a hypoglycemic drug that can maintain the efficacy of PI3K inhibitors. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a combination of a glucokinase activator and a PI3K inhibitor. It is found that the glucokinase activator can not only alleviate the hyperglycemia caused by the PI3K inhibitor, but also enhance the antitumor effect of the PI3K inhibitor, thereby promoting the further clinical application of the PI3K inhibitor.

[0005] The present application provides a combination of a glucokinase activator and a PI3K inhibitor, comprising a pharmaceutical composition of a glucokinase activator or a pharmaceutically acceptable salt thereof and a PI3K inhibitor or a pharmaceutically acceptable salt thereof.

[0006] Preferably, the glucokinase activator is selected from one or more of dorzagliatin (HMS5552), HM-002-1005, TTP399, PB-201 and SY-004.

[0007] Preferably, the PI3K inhibitor is selected from one or more of a PI3K alpha inhibitor, a PI3K beta inhibitor, a PI3K gamma inhibitor, a PI3K delta inhibitor and a pan-PI3K isoform inhibitor.

[0008] Preferably, the PI3K inhibitor is selected from one or more of Inavolisib, Idelalisib (GS-1101 / CAL-101), Copanlisib (BAY 806946), Duvelisib (IPI-145), Alpelisib (BYL719), GDC-0941 BKM120, XL147, PX-866, CH5132799, MLN1117, AZD8186, SAR260301, GSK2636771, AMG319, GS-9820, GDC-0032 and GDC-0084.

[0009] Preferably, the dosage form of the composition is tablet, capsule, injection, inhalation or spray.

[0010] Preferably, the administration of the composition is oral, intravenous injection, intratumoral injection or subcutaneous injection.

[0011] Preferably, the administration of the composition is simultaneous administration or sequential administration.

[0012] Preferably, the glucokinase activator or a pharmaceutically acceptable salt thereof and the PI3K inhibitor or a pharmaceutically acceptable salt thereof in the composition are both in a therapeutically effective amount.

[0013] The present application also provides a use of a combination of a glucokinase activator and a PI3K inhibitor in the preparation of a medicament for preventing or treating a tumor.

[0014] Preferably, the tumor comprises one or more of lung cancer, liver cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, myeloma, intestinal cancer, lymphoma, prostate cancer, pancreatic cancer, ovarian cancer, adrenal cancer, thyroid cancer, germ cell tumor, uterine cancer, retinoblastoma, cervical cancer, bone cancer, laryngeal cancer, urinary system tumor, oral cancer, rhabdomyosarcoma, tongue cancer, nasopharyngeal cancer, brain cancer, leukemia, synovioma, melanoma, breast cancer.

[0015] The "therapeutically effective amount" of the present application refers to an amount sufficient to prevent, arrest or delay the disease, obtain or at least partially obtain the desired effect. The amount effective for therapeutic use is determined by a clinician, researcher, veterinarian, etc. will depend on a variety of factors, including but not limited to the species of mammal (including humans), its age, size, body weight, gender and overall health, the severity of the cancer involved, the mode of administration of the drug, the time, route and rate of excretion, the bioavailability characteristics of the preparation administered, the selected dosage regimen, the use of concurrent medication, and whether other treatments are administered simultaneously, and other factors such as the adjustment of the amount.

[0016] The "pharmaceutically acceptable salt" described in the present application refers to the salt formed by the existing acidic functional group and the appropriate inorganic or organic cation (base), and includes all forms of salts.

[0017] Advantageous effects

[0018] The present application finds that the glucokinase activator can not only alleviate the hyperglycemia caused by the PI3K inhibitor, but also enhance the anti-tumor effect of the PI3K inhibitor, thus promoting the further clinical application of the PI3K inhibitor. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Exogenous hyperinsulinemia reduces the anti-tumor activity of PI3K inhibitors. (A) CCK-8 proliferation capacity assay of tumor cells after insulin and PI3K inhibitor treatment. t-test analysis: ****p<0.0001, ***p<0.001. (B-C) EdU detection results show the changes in tumor cell proliferation in SKOV3 and OVCAR3 cell lines after insulin and PI3K inhibitor treatment. Data are expressed as mean ± SD; statistical significance was determined by t-test analysis: ***p<0.001, **p<0.01.

[0020] Figure 2 Dorzagliatin reduces PI3K inhibitor-induced hyperglycemia and hyperinsulinemia. (A) Changes in blood glucose in the BYL719, Dorz (dorzagliatin), Dorz+BYL719 groups; (B) C-peptide levels in the blood of BALB / C mice 8 hours after treatment. Data are expressed as mean ± SEM; statistical significance was determined by t-test analysis: *p<0.05.

[0021] Figure 3 Dorzagliatin enhances the anti-cancer effect of PI3K inhibitors. (A) Tumor images of the OVCAR3 xenograft tumor model in BALB / c mice after treatment with BYL719 or combination therapy. (B) Tumor growth curve of the OVCAR3 xenograft model after administration of BYL719 or combination therapy. (C) Tumor weights of different treatment groups. (D) Relative body weight changes (%) of mice during treatment. (E) Liver index was calculated at the end of the experiment to assess in vivo toxicity. Data are expressed as mean ± SD; differences were statistically significant using one-way ANOVA: *p<0.05, **p<0.01, ****p<0.0001. DETAILED DESCRIPTION

[0022] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. Furthermore, it should be understood that those skilled in the art can make various modifications or changes to the application after reading the content of the application, and these equivalent forms also fall within the scope defined by the appended claims.

[0023] Example 1

[0024] 1. Methods: The interaction of exogenous hyperinsulinemia with PI3K inhibitors was comprehensively investigated in SKOV3 and OVCAR3 ovarian cancer cell lines. CCK-8 and EdU assays were used to determine the effect of this interaction on cell proliferation. In addition, the hypoglycemic effect of dorzagliatin was evaluated in a PI3K inhibitor-induced hyperglycemic mouse model. The in vivo tumor growth inhibition effect of dorzagliatin in combination with PI3K inhibitors was evaluated using a cell line-derived xenograft (CDX) model.

[0025] 2. Results:

[0026] 2.1 Exogenous hyperinsulinemia reduces the antitumor activity of PI3K inhibitors

[0027] Clinical findings have shown that PI3K inhibitors can cause insulin resistance, leading to hyperglycemia and compensatory hyperinsulinemia. It was hypothesized that PI3K inhibitor-induced hyperinsulinemia might reactivate cell proliferation through the AKT / INSR / mTOR signaling pathway, thereby counteracting its antitumor effect. To investigate the effect of hyperinsulinemia on the efficacy of PI3K inhibitors, CCK-8 and EdU cell proliferation assays were performed on SKOV3 and OVCAR3 ovarian cancer cell lines treated with insulin (10 ng / ml) and BYL719 (5 μM). The results showed that the increase in insulin levels significantly impaired the antiproliferative effect of BYL719, as insulin-treated tumor cells proliferated more than BYL719-treated tumor cells alone ( Figure 1 A). Notably, in the EdU experiment, while SKOV3 cells showed a significant increase in proliferation under both vehicle and PI3K inhibitor treatment in the presence of insulin, OVCAR3 cells showed a statistically significant increase in proliferation only in the PI3K inhibitor-treated group, with no significant change in the blank control-treated cells ( Figure 1 B-C). These findings suggest that hyperinsulinemia, which is usually secondary to PI3K inhibitor-induced hyperglycemia, can impair the therapeutic effect of PI3K inhibitors by promoting tumor cell proliferation.

[0028] 2.2. Dorzagliatin reduces PI3K inhibitor-induced hyperglycemia and hyperinsulinemia

[0029] To determine whether dorzagliatin can reduce PI3K inhibitor-induced hyperglycemia, a PI3K inhibitor-induced metabolic dysfunction mouse model was used. Mice treated with BYL719 alone had significantly elevated blood glucose levels within 1 hour of dosing. In contrast, the combination of dorzagliatin with PI3K inhibitor significantly reduced blood glucose levels compared to the PI3K inhibitor alone group ( Figure 2 A).

[0030] Serum c-peptide levels were significantly lower in the dorzagliatin-treated group compared to the PI3K inhibitor alone group 8 hours after dosing ( Figure 2 B). These results suggest that dorzagliatin can effectively alleviate PI3K inhibitor-induced hyperglycemia and hyperinsulinemia, enhancing the anti-tumor efficacy of PI3K inhibitors by mitigating the negative effects of elevated insulin levels.

[0031] 2.3 dorzagliatin enhances the anti-cancer effect of PI3K inhibitors

[0032] To assess whether dorzagliatin can enhance the anti-tumor efficacy of PI3K inhibitors, the tumor volumes of mice treated with BYL719 alone and in combination with BYL719 were compared. The combination therapy group had significantly reduced tumor growth compared to the BYL719 alone treatment group ( Figure 3 A-C), indicating that dorzagliatin and PI3K inhibitors synergistically inhibit tumors. Relative body weight changes in all treatment groups remained within 15% of baseline, indicating good tolerability of the treatment ( Figure 3 D). Given the potential toxicity of glucokinase activators, as reported in previous studies, systemic toxicity was further assessed by calculating the liver index, calculated as: Liver index (%) = (liver weight / mouse body weight) x 100%. The results showed no significant difference in liver index between groups, indicating no systemic toxicity in major organs ( Figure 3 E). These findings support the safety and reliability of combination therapy.

[0033] 3. Conclusion:

[0034] Insulin attenuates the anti-proliferative effect of PI3K inhibitors. In a hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to the control group. The tumor volume in the combination therapy group (dorzagliatin + PI3K inhibitor) CDX model was significantly reduced. Dorzagliatin not only alleviates hyperglycemia but also enhances the anti-tumor effect of PI3K inhibitors, which has been proven in clinical trials.

[0035] It is important to underline that, in the experiments, only dorzagliatin has been used, but according to the common knowledge of the person skilled in the art, other glucokinase activators should have similar or analogous effects, after having clarified the above mechanisms.

Claims

1. A combination of a glucokinase activator and a PI3K inhibitor, characterized in that: A pharmaceutical composition comprising a glucokinase activator or a pharmaceutically acceptable salt thereof and a PI3K inhibitor or a pharmaceutically acceptable salt thereof; the glucokinase activator is dorzagliatin; the PI3K inhibitor is alpelisib.

2. The composition of claim 1, wherein: The dosage form of the composition is a tablet, a capsule, an injection, an inhalant or a spray.

3. The composition of claim 1, wherein: The administration mode of the composition is oral, intravenous injection, intratumoral injection or subcutaneous injection.

4. The composition of claim 1, wherein: The administration mode of the composition is simultaneous administration or sequential administration.

5. The composition of claim 1, wherein: The glucokinase activator or a pharmaceutically acceptable salt thereof and the PI3K inhibitor or a pharmaceutically acceptable salt thereof in the composition are both therapeutically effective amounts.

6. Use of the combination of a glucokinase activator and a PI3K inhibitor according to claim 1 in the preparation of a medicament for preventing or treating a tumor.

7. Use according to claim 6, characterized in that: The tumor includes one or several of lung cancer, liver cancer, stomach cancer, pancreatic cancer, skin cancer, head and neck cancer, myeloma, intestinal cancer, lymphoma, prostate cancer, pancreatic cancer, ovarian cancer, adrenal cancer, thyroid cancer, germ cell tumor, uterine cancer, retinoblastoma, cervical cancer, bone cancer, laryngeal cancer, urinary system tumor, oral cancer, rhabdomyosarcoma, tongue cancer, nasopharyngeal cancer, brain cancer, leukemia, synovioma, melanoma and breast cancer.

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