CN107137403B

CN107137403B - Application of PI3K/MTOR inhibitor in preparation of medicine for treating pancreatic cancer

Info

Publication number: CN107137403B
Application number: CN201710116510.9A
Authority: CN
Inventors: 孙飘扬; 曹国庆; 唐蜜; 杨昌永; 张连山
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2016-03-01
Filing date: 2017-02-28
Publication date: 2021-07-02
Anticipated expiration: 2037-02-28
Also published as: CN107137403A

Abstract

The invention relates to application of a PI3K/MTOR inhibitor in preparing a medicament for treating pancreatic cancer. The PI3K/MTOR inhibitor can be used in combination with a Hedgehog inhibitor. The invention also relates to a pharmaceutical composition containing the two inhibitors.

Description

Application of PI3K/MTOR inhibitor in preparation of medicine for treating pancreatic cancer

Technical Field

The invention relates to application of a PI3K/MTOR inhibitor in preparing a medicament for treating pancreatic cancer.

Background

Pancreatic cancer is a malignant tumor of the digestive tract that is highly malignant and difficult to diagnose and treat, and about 90% of pancreatic cancers are ductal adenocarcinomas originating from the epithelium of the glandular duct. The incidence and mortality of the Chinese pancreatic cancer are obviously increased in 2000-2011. Survival rate < 1% for 5 years is one of the worst-prognosis malignancies. The early diagnosis rate of pancreatic cancer is low, the operative mortality rate is high, and the cure rate is low. The incidence rate of the disease is higher for men than for women, the ratio of men to women is 1.5-2: 1, male patients are far more common than women before menopause, and the incidence rate of postmenopausal women is similar to that of men.

CN103282363A discloses a PI3K/mTOR dual inhibitor, which has strong inhibition effect on PI3K and mTOR kinase, the compounds are shown in the following formula (I) and have the chemical name of 1-methyl-3- [5- [ 3-methyl-2-oxygen-1- [3- (trifluoromethyl) phenyl ] -2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-8-yl ] pyridin-2-yl ] urea, and the possibility of application of the compounds in treating melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver, kidney, bladder, prostate, breast and pancreatic cancers and sarcomas, primary and recurrent solid tumors of skin, colon, thyroid, lung and ovary or leukemia is also indicated.

CN103261198A discloses a class of Hedgehog signaling pathway inhibitors, which includes compounds of the following formula (II) with the chemical name N- (2-ethyl-5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b ] pyridazin-2-yl) phenyl) -1-methylcyclopropylformamide, and discloses that the Hedgehog signaling pathway may be associated with glioblastoma, basal cell carcinoma and pancreatic cancer.

None of the above documents disclose the use of specific combinations of PI3K/mTOR with Hedgehog inhibitors for the treatment of pancreatic cancer.

Disclosure of Invention

The invention surprisingly discovers that the PI3K/mTOR inhibitor has good treatment effect on pancreatic cancer. In a preferred embodiment of the invention, the PI3K/mTOR inhibitor is a compound of formula (I) as follows or a pharmaceutically acceptable salt thereof. In the present invention, the amount of said PI3K/MTOR inhibitor may be in the range of 0.1 to 1000mg/kg, preferably 1 to 100mg/kg, more preferably 5 to 20mg/kg, said amount being measured as compound (I).

In a preferred embodiment of the present invention, the PI3K/MTOR inhibitor is used in combination with a Hedgehog signaling pathway inhibitor, which is more effective for pancreatic cancer, and particularly preferably, the Hedgehog signaling pathway inhibitor is a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof. In the present invention, the amount of said Hedgehog signaling pathway inhibitor may be in the range of 1-1000 mg/kg, preferably 5-500 mg/kg, more preferably 10-200 mg/kg, most preferably 20-150 mg/kg, said amount being measured as compound (II). In the present invention, the combined use means that two or more drugs are administered to a subject in the same administration cycle, but whether they are administered simultaneously or not is not limited, and may be preceded and followed by a certain time interval.

The pharmaceutically acceptable salts of the compounds of formula (I) and formula (II) in the present invention may be selected from various inorganic or organic acid salts known in the art.

The compounds of formula (I) and (II) or their pharmaceutically acceptable salts can also be formulated with pharmaceutically acceptable carriers into compositions well known in the art, such as tablets, capsules, granules, injections, etc. The invention also relates to the use of a composition containing a compound selected from formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of pancreatic cancer as described above.

Drawings

FIG. 1 shows the therapeutic effect of compounds (I), (II) alone or in combination on human pancreatic cancer BXPC-3 nude mouse transplantable tumors.

FIG. 2 shows the therapeutic effect of compounds (I), (II) alone or in combination on human pancreatic cancer BXPC-3 nude mouse transplantable tumors (tumor photographs).

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1: evaluating the efficacy of the compound (I) and the compound (II) alone or in combination on human pancreatic cancer BXPC-3 nude mouse transplantable tumors.

1 test drugs

The test compound (I) and the compound (II) were synthesized in accordance with the disclosures of CN103282363A and CN103261198A, respectively. The preparation method comprises the following steps: compound (I) was formulated with 70% PEG 400 and compound (II) was formulated with 30% PEG 400.

2 laboratory animals

BALB/cA-nude mice, 6-7 weeks old, purchased from Shanghai Spiker laboratory animals, Inc. Certificate number: SCXK (Shanghai) 2007 & 0005. A breeding environment: SPF grade.

3 Experimental procedures

The nude mouse is inoculated with BXPC-3 cells of human pancreatic cancer subcutaneously until the tumor grows to 100-200mm³Thereafter, the animals were randomly assigned (D0). The dosage and schedule of administration are shown in table 1. Tumor volumes were measured 2-3 times a week, mice weighed, and data recorded. Tumor volume (V) was calculated as:

V＝1/2×a×b²wherein a and b represent length and width, respectively.

T/C(％)＝(T-T₀)/(C-C₀) X 100 where T, C is the tumor volume at the end of the experiment; t is₀、C₀Tumor volume at the beginning of the experiment.

4 results

The compound (II) (75mg/kg, PO, QD X16) and the compound (I) (10mg/kg, PO, QD X16) have certain inhibition effect on the growth of human pancreatic cancer BxPC-3 nude mouse transplanted tumor, and the inhibition rates are 33% and 40% respectively; the combination of the two drugs has obviously enhanced tumor inhibition effect, and the tumor inhibition rate reaches 77 percent, which is obviously better than the curative effect of the single use of the two drugs).

TABLE 1 curative effects of Compound (I), Compound (II) alone or in combination on human pancreatic cancer BxPC-3 nude mouse transplantable tumor

D0 time to first dose. P-value refers to comparison to control; p <0.05vs compound (I) + compound (II), Student's t' assay. Control group n is 10 and treatment group n is 6.

5 conclusion

The compounds (I) and (II) have certain inhibition effect on the growth of human pancreatic cancer BxPC-3 nude mouse transplantation tumor when used singly, and the inhibition effect is obviously enhanced when the compounds (I) and (II) are used together.

Claims

Use of a PI3K/MTOR inhibitor and a Hedgehog signaling pathway inhibitor in the preparation of a medicament for treating pancreatic cancer, wherein the PI3K/MTOR inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

the Hedgehog signal pathway inhibitor is a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof,
2. the use according to claim 1, wherein the amount of PI3K/MTOR inhibitor is 0.1-1000 mg/kg.
3. The use according to claim 2, wherein the amount of PI3K/MTOR inhibitor is 1-100 mg/kg.
4. The use according to claim 2, wherein the amount of PI3K/MTOR inhibitor is 5-20 mg/kg.
5. The use of claim 1, wherein the Hedgehog signaling pathway inhibitor is present in an amount of 1-1000 mg/kg.
6. The use of claim 5, wherein the Hedgehog signaling pathway inhibitor is present in an amount of 5-500 mg/kg.
7. The use of claim 5, wherein the Hedgehog signaling pathway inhibitor is present in an amount of 10-200 mg/kg.
8. The use of claim 5, wherein the Hedgehog signaling pathway inhibitor is present in an amount of 20-150 mg/kg.
9. A pharmaceutical composition for treating pancreatic cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as set forth in claim 1 and a compound of formula (II) or a pharmaceutically acceptable salt thereof as set forth in claim 1, and a pharmaceutically acceptable carrier.