Composition of glucokinase activator and PI3K inhibitor

Abstract

The invention relates to a composition of a glucokinase activator and a PI3K inhibitor. It is found that the glucokinase activator not only can relieve hyperglycemia caused by the PI3K inhibitor, but also can enhance the anti-tumor effect of the PI3K inhibitor, and further clinical application of the PI3K inhibitor is promoted.

Description

Technical Field

[0001] The present invention belongs to the field of cancer treatment, and particularly relates to a composition of a glucokinase activator and a PI3K inhibitor. Background Art

[0002] In peripheral tissues, PI3K inhibitors have become viable targets for novel anti-cancer therapies. Successful drug designs have yielded three classes of potent and selective small molecule inhibitors, which 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 advanced into clinical trials as new anti-cancer drugs (Akinleye et al., Journal of Hematology & Oncology, 6:88, 2013).

[0003] However, common hyperglycemic target adverse reactions pose a major challenge to the clinical application of PI3K inhibitors. There is an urgent need to discover an anti-hyperglycemic drug that can maintain the efficacy of PI3K inhibitors. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a composition of a glucokinase activator and a PI3K inhibitor, and it is found 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, promoting the further clinical application of the PI3K inhibitor.

[0005] The present invention provides a composition of a glucokinase activator and a PI3K inhibitor, which is a pharmaceutical composition comprising 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 the following: dorzagliatin (HMS5552), HM-002-1005, TTP399, PB-201, and SY-004.

[0007] Preferably, the PI3K inhibitor is selected from one or more of the following: PI3Kα inhibitor, PI3Kβ inhibitor, PI3Kγ inhibitor, PI3Kδ inhibitor, and pan-PI3K isoform inhibitor.

[0008] Preferably, the PI3K inhibitor is selected from one or more of the following: Inavolisib, Idelalisib (GS-1101 / CAL-101), Copanlisib (BAY806946), 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, inhalant, or spray.

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

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

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

[0013] The present invention also provides the use of a composition of a glucokinase activator and a PI3K inhibitor in the preparation of a drug for preventing or treating tumors.

[0014] Preferably, the tumors include one or more of lung cancer, liver cancer, gastric 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.

[0015] As used herein, "therapeutically effective amount" refers to an amount sufficient to prevent, arrest, or delay a disease and obtain or at least partially obtain the desired effect. The amount determined to be effective for therapeutic use by clinicians, researchers, veterinarians, etc. will depend on various factors, including but not limited to the species of mammal (including humans), its age, size, weight, gender, and overall health status, the severity of the cancer involved, the mode of drug administration, the time of administration, the route and excretion rate, the bioavailability characteristics of the administered formulation, the selected dosage regimen, the use of concomitant medications, and other treatments administered simultaneously.

[0016] As used herein, "pharmaceutically acceptable salts" refers to salts formed by acidic functional groups present with appropriate inorganic or organic cations (bases), and includes all forms of salts.

[0017] Beneficial effects

[0018] The present invention discovers that glucokinase activators can not only alleviate hyperglycemia caused by PI3K inhibitors, but also enhance the anti-tumor effect of PI3K inhibitors, promoting the further clinical application of PI3K inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0020] Figure 2 Shows that dorzagliatin reduces PI3K inhibitor-induced hyperglycemia and hyperinsulinemia. (A) Blood glucose changes in the BYL719, Dorz (dorzagliatin), Dorz+BYL719 groups; (B) Blood C-peptide levels in 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 Shows that dorzagliatin can enhance 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 curves of the OVCAR3 xenograft model after treatment with BYL719 or combination therapy. (C) Tumor weights of different treatment groups. (D) Relative body weight changes (%) of mice during treatment. (E) The liver index was calculated at the end of the experiment to evaluate in vivo toxicity. Data are expressed as mean ± SD; one-way ANOVA was used to determine statistical significance: *p < 0.05, **p < 0.01, ****p < 0.0001. DETAILED DESCRIPTION OF THE INVENTION

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

[0023] Example 1

[0024] 1. Method: The interaction between exogenous hyperinsulinemia and PI3K inhibitors in SKOV3 and OVCAR3 ovarian cancer cell lines was comprehensively studied. 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 mouse model of hyperglycemia induced by PI3K inhibitors. A cell line-derived xenograft (CDX) model was used to evaluate the in vivo tumor growth inhibitory effect of dorzagliatin combined with PI3K inhibitors.

[0025] 2. Results:

[0026] 2.1 Exogenous hyperinsulinemia reduces the anti-tumor activity of PI3K inhibitors

[0027] Clinically, it has been found that PI3K inhibitors can cause insulin resistance, leading to hyperglycemia and compensatory hyperinsulinemia. It is hypothesized that hyperinsulinemia induced by PI3K inhibitors may reactivate cell proliferation through the AKT / INSR / mTOR signaling pathway, thereby offsetting its anti-tumor 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 elevated insulin levels significantly impaired the anti-proliferative effect of BYL719, as tumor cells treated with insulin had increased proliferation compared to those treated with BYL719 alone ( Figure 1 A). Notably, in the EdU assay, although SKOV3 cells showed a significant increase in proliferation under both vehicle and PI3K inhibitor treatment conditions in the presence of insulin, the proliferation of OVCAR3 cells was significantly increased only in the PI3K inhibitor treatment group and not significantly changed in the cells treated with the blank control ( Figure 1 B-C). These findings suggest that hyperinsulinemia, which is usually secondary to hyperglycemia induced by PI3K inhibitors, may 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 mouse model of PI3K inhibitor-induced metabolic dysfunction was used. Mice treated with BYL719 alone showed a significant increase in blood glucose levels within 1 hour after dosing. In contrast, compared with the group treated with only the PI3K inhibitor, the combination of dorzagliatin and the PI3K inhibitor significantly reduced blood glucose levels ( Figure 2 A).

[0030] Eight hours after dosing, the serum C-peptide level in the dorzagliatin treatment group was significantly lower than that in the group treated with only the PI3K inhibitor ( Figure 2 B). These results indicate that dorzagliatin can effectively alleviate PI3K inhibitor-induced hyperglycemia and hyperinsulinemia, and enhance the anti-tumor efficacy of the PI3K inhibitor by reducing the negative impact of elevated insulin levels.

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

[0032] To evaluate 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. Compared with the group treated with BYL719 alone, tumor growth in the combination treatment group was significantly reduced ( Figure 3 A-C), indicating that dorzagliatin and the PI3K inhibitor synergistically inhibit tumors. The relative body weight changes in all treatment groups remained within 15% of the baseline, indicating good tolerance to the treatment ( Figure 3 D). Given the potential toxicity of glucose kinase activators, as reported in previous studies, systemic toxicity was further evaluated by calculating the liver index, with the formula: Liver index (%) = (liver weight / mouse body weight) × 100%. The results showed no significant differences in liver indices among the groups, indicating no systemic toxicity in the major organs ( Figure 3 E). These findings support the safety and reliability of the combination treatment.

[0033] 3. Conclusion:

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

[0035] It should be emphasized that although only dorzagliatin was used in the experiment, according to the general knowledge of those skilled in the art, after clarifying the above mechanism, other glucokinase activators should also have similar or comparable effects.

Claims

1. A composition 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.

2. The composition according to claim 1, wherein: The glucokinase activator is selected from one or more of the following: dorzagliatin, HM-002-1005, TTP399, PB-201, and SY-004.

3. The composition according to claim 1, wherein: The PI3K inhibitor is selected from one or more of the following: PI3Kα inhibitor, PI3Kβ inhibitor, PI3Kγ inhibitor, PI3Kδ inhibitor, and pan-PI3K isoform inhibitor.

4. The composition according to claim 1 or 3, characterized in that: The PI3K inhibitor is selected from one or more of the following: inalidef, idelalisib, copanlisib, duvelisib, alpelisib, GDC-0941 (BKM120), XL147, PX-866, CH5132799, MLN1117, AZD8186, SAR260301, GSK2636771, AMG319, GS-9820, GDC-0032, and GDC-0084.

5. The composition according to claim 1, wherein: The dosage form of the composition is tablet, capsule, injection, inhalant, or spray.

6. The composition according to claim 1, characterized in that: The administration method of the composition is oral administration, intravenous injection, intratumoral injection, or subcutaneous injection.

7. The composition according to claim 1, characterized in that: The administration mode of the composition is simultaneous administration or sequential administration.

8. The composition according to claim 1, characterized in that: Both the glucokinase activator or a pharmaceutically acceptable salt thereof and the PI3K inhibitor or a pharmaceutically acceptable salt thereof in the composition are in therapeutically effective amounts.

9. Use of a composition of a glucokinase activator and a PI3K inhibitor as described in claim 1 in the preparation of a drug for preventing or treating tumors.

10. The use according to claim 9, wherein: The tumors include one or more of lung cancer, liver cancer, gastric 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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