WO2022012308A1 - 索拉非尼、瑞戈非尼及其类似物或衍生物的新应用 - Google Patents

索拉非尼、瑞戈非尼及其类似物或衍生物的新应用 Download PDF

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WO2022012308A1
WO2022012308A1 PCT/CN2021/102607 CN2021102607W WO2022012308A1 WO 2022012308 A1 WO2022012308 A1 WO 2022012308A1 CN 2021102607 W CN2021102607 W CN 2021102607W WO 2022012308 A1 WO2022012308 A1 WO 2022012308A1
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sorafenib
drug
resistant
regorafenib
hel
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PCT/CN2021/102607
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邓沱
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中南大学湘雅二医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention belongs to the technical field of medicine, and specifically relates to the new application of sorafenib, regorafenib and their analogs or derivatives, especially the preparation of sorafenib, regorafenib and their analogs or derivatives in the preparation of therapeutic Drug use in polycythemia vera and ruxolitinib-resistant myeloproliferative neoplasms.
  • Myeloproliferative neoplasms refer to a group of neoplastic diseases caused by the clonal proliferation of relatively mature one-line or multi-lineage myeloid cells.
  • the 2016 World Health Organization (WHO) classification of myeloid neoplasms revised to include the following myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), BCR-ABL 1+ ; chronic neutrophilic leukemia ); polycythemiavera (PV); primary myelofibrosis (PMF); essential thrombocythemia (ET); chronic eosinophilic leukemia, n.o.
  • MPNS unclassifiable.
  • PV, ET, and PMF are classified as Philadelphia-negative classical MPNs, and clinically manifest as one or more blood cell hyperplasia with liver, spleen, or lymphadenopathy.
  • MPNS is a clonal hematopoietic stem cell disease.
  • the main gene mutations that drive the disease include JAK2/V617F, CALR, and MPL mutations, of which JAK2/V617F mutation is the most common type, which can be found in 95% of PV, 50-60% of ET and 55-65% of PMF patients. Insertion or deletion mutations in exon 12 of JAK2 can be found in approximately 3% of PV patients.
  • the goal of treatment in patients with PV and ET is to avoid thrombotic and bleeding complications.
  • the main goal of PMF treatment is to prolong survival. If conditions permit, allogeneic stem-cell transplantation (AlloSCT) should be used to achieve the purpose of cure; if survival or cure cannot be prolonged, the main goal of treatment is remission symptoms and improved quality of life.
  • AlloSCT allogeneic stem-cell transplantation
  • MPNs are clinically diagnosed according to the "2016 World Health Organization Classification of Myeloid Tumors and Acute Leukemia", risk stratification and corresponding treatment measures are taken.
  • Ruxolitinib as a JAK1/JAK2 inhibitor, is approved by the FDA for first-line treatment of intermediate and high-risk myelofibrosis (MF) including primary myelofibrosis and post-polycythemia vera myelofibrosis Myelofibrosis after fibrosis and essential thrombocythemia. And as a second-line drug for hydroxyurea (Hydroxyurea, HU) resistant or intolerable PV patients. Phase II and Phase III clinical trial results suggest that RUX can reduce spleen volume and reduce symptoms in patients with intermediate and high-risk MF and PV compared with best available therapy (BAT).
  • BAT best available therapy
  • RUX as a type I JAK2 inhibitor, represents an important advance in the treatment of MPNs, but it has not lived up to high expectations.
  • Bone marrow transplantation is the only cure for MPNs, but there are still some issues that need to be addressed.
  • the choice of transplantation modality and protocol is uncertain, and the choice of allogeneic or haploidentical transplantation is unclear.
  • transplantation-related mortality and the long-term nature of myeloproliferative tumors must be considered when selecting transplantation.
  • bone marrow transplantation is mainly used to treat high-risk myelofibrosis patients, but the timing of bone marrow transplantation for patients with other types of MPNs needs to be further explored and confirmed by research. Bone marrow transplants are expensive and, in the current medical environment, are not an option for most patients.
  • ruxolitinib is a milestone drug in the treatment of MPNs, but the lack of good therapeutic drugs after patients develop resistance to it is a major challenge in the current treatment of MPNs. There are currently no drugs available for ruxolitinib-resistant patients.
  • the purpose of the present invention is to provide a drug for myeloproliferative tumors, especially for ruxolitinib-resistant patients, in view of the problems existing in the prior art.
  • Sorafenib is a small molecule compound that inhibits tumor cell proliferation, angiogenesis and increases apoptosis in a wide range of tumor models.
  • As an oral receptor tyrosine kinase inhibitor it inhibits factors involved in tumorigenesis and tumor progression, such as Raf serine/threonine kinase and receptor tyrosine kinases (vascular endothelial growth factor receptor 1, 2, 3 and platelet-derived growth factor-beta, Flt-3 and c-kit).
  • Sorafenib is approved by the US FDA for the treatment of advanced inoperable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC), as well as advanced radioiodine-refractory differentiated thyroid cancer (radioiodine-referectory) differentiated thyroid cancer, RRDTC).
  • HCC advanced inoperable hepatocellular carcinoma
  • RRC advanced renal cell carcinoma
  • RRDTC advanced radioiodine-refractory differentiated thyroid cancer
  • the molecular formula of Sorafenib is C 21 H 16 ClF 3 N 4 O 3 , the molecular weight is 464.83, and the structural formula is shown in formula I.
  • the sorafenib analog, Regorafenib has a molecular formula of C 21 H 15 ClF 4 N 4 O 3 , a molecular weight of 482.82, and a structural formula as shown in formula II.
  • the inhibitory effect of sorafenib on myeloproliferative tumor cells was clarified by using a cell line model.
  • the present invention establishes two common drug-resistant cell models HEL PE and HEL RE based on HEL cells (Human erythroleukemia cell line), a commonly used human myeloproliferative tumor cell line containing JAK2-V617F mutation .
  • HEL PE model is the HEL-persistent model, and the construction method is to use more than High-concentration ruxolitinib treatment with a concentration of 100 times the IC50 of cells For cells, change the medium every two days, the cells that cannot tolerate it die quickly, and the expanded cells are DTP (drug-tolerant-persisters), and this cell subset is difficult to be killed by anti-tumor drugs.
  • Another drug resistance model is HEL RE , or HEL-resistant model, which is constructed by using less than The IC50 concentration of the cells started to be added and gradually increased to a high concentration to maintain the cells from being killed.
  • the present invention treats two drug-resistant cell lines with increasing concentrations of sorafenib, and detects cell proliferation by CellTiter-LumiTM luminescence assay. The results showed that sorafenib could successfully inhibit the proliferation of cells in the HEL PE model and the HEL RE model.
  • the present invention uses increasing concentrations of sorafenib to treat two drug-resistant cell lines, and uses AnnexinV-PI staining to detect the apoptosis of cells by flow cytometry.
  • sorafenib could promote the apoptosis of cells in HEL PE model and HEL RE model.
  • the present invention treats HEL RE resistant cell lines with increasing concentrations of regorafenib (sorafenib analog), and detects cell proliferation by CellTiter-Lumi TM luminescence assay, while using AnnexinV-PI staining The apoptosis of cells was detected by flow cytometry. The results show that the non-Nicole Ruige successfully inhibit proliferation of HEL RE model cells and promote apoptosis HEL RE model.
  • sorafenib, regorafenib and their analogs or derivatives can be used for the treatment of ruxolitinib-resistant MPN diseases.
  • the present invention uses increasing concentrations of sorafenib, regorafenib and their analogs or derivatives to treat HEL, a human cell model commonly used in the study of PV, and detect by CellTiter-Lumi TM luminescence method proliferation of cells.
  • HEL sorafenib, regorafenib and their analogs or derivatives
  • the present invention provides the application of sorafenib, regorafenib and their analogs or derivatives in the preparation of medicines for inhibiting the proliferation of HEL cells.
  • the present invention uses increasing concentrations of sorafenib, regorafenib and their analogs or derivatives to treat HEL, a human cell model commonly used to study PV, and use AnnexinV-PI staining to detect the flow of cells. apoptosis.
  • sorafenib, regorafenib and their analogs or derivatives could promote the apoptosis of HEL cells. Therefore, the present invention provides the application of sorafenib, regorafenib and their analogs or derivatives in the preparation of medicines for promoting the apoptosis of HEL cells.
  • sorafenib, regorafenib and their analogs or derivatives can be used to treat myeloproliferative tumors, especially polycythemia vera, by inhibiting the proliferation of HEL cells and promoting the apoptosis of HEL cells.
  • the present invention provides applications of sorafenib, regorafenib and their analogs or derivatives in the preparation of medicaments for the treatment of myeloproliferative tumors.
  • the myeloproliferative tumor is polycythemia vera or a drug-resistant myeloproliferative tumor.
  • the drug-resistant myeloproliferative tumor is a ruxolitinib-resistant myeloproliferative tumor.
  • the drug-resistant myeloproliferative neoplasm is drug-resistant polycythemia vera, drug-resistant primary myelofibrosis, and drug-resistant essential thrombocythemia disease.
  • the drugs include sorafenib, regorafenib and their analogs or derivatives.
  • the drugs include sorafenib analogs: Regorafenib, which differs from sorafenib in that one H in sorafenib becomes in regorafenib.
  • Regorafenib is an oral tyrosine kinase inhibitor approved for the treatment of refractory metastatic colorectal cancer, advanced gastrointestinal stromal tumors previously treated with imatinib and sunitinib, and unresectable hepatocellular carcinoma that progressed after use of sorafenib.
  • the sorafenib used is specifically sorafenib mesylate.
  • the medicine also includes pharmaceutically acceptable excipients.
  • the drug can be any dosage form in the current pharmaceutical field, including oral preparations or injection preparations.
  • Each pharmaceutical dosage form can be prepared by selecting appropriate acceptable excipients according to the actual needs of the dosage form, which belongs to the conventional dosage form preparation technology in the art. Such as capsules, tablets, injection powder and so on.
  • the present invention provides applications of sorafenib, regorafenib and their analogs or derivatives in the preparation of medicaments for the treatment of myeloproliferative tumors.
  • the myeloproliferative tumor is polycythemia vera or ruxolitinib-resistant myeloproliferative tumor.
  • sorafenib, regorafenib and their analogs or derivatives in the treatment of polycythemia vera provides a new treatment approach for the majority of patients with polycythemia vera, and provides more choices for clinicians and patients.
  • sorafenib, regorafenib and their analogs or derivatives can provide patients with continued oral drug therapy and avoid bone marrow transplantation.
  • Sorafenib, regorafenib and their analogs or derivatives can be chemically synthesized, and the cost is lower than that of biological preparations. And it has been approved by FDA and NMPA for clinical treatment. It has fewer and milder side effects, is well tolerated by clinical patients, and has a lighter burden on patients.
  • Figure 1 shows the results of the establishment of the drug-resistant cell models HEL PE and HEL RE in Example 1; a is the successful construction of the HEL-persistent model; b is the successful construction of the HEL-resistant model;
  • Figure 2 shows the results of cell proliferation detected by the CellTiter-Lumi TM luminescence method when two drug-resistant cell lines were treated with sorafenib in Example 2; a is the result of cell proliferation in the HEL-persistent model; b is the HEL-resistant model cell Proliferation result graph;
  • Fig. 3 shows the results of flow detection of apoptosis of two drug-resistant cell lines treated with sorafenib in Example 3 and stained with AnnexinV-PI; a is the result of cell apoptosis in HEL-persistent model; b is HEL- The result of apoptosis of resistant model cells;
  • Figure 4 shows the results of Sorafenib-treated PV cell lines in Example 4, and cell proliferation detected by CellTiter-Lumi TM luminescence method
  • Fig. 5 shows the results of flow cytometry of apoptosis of PV cell lines treated with sorafenib in Example 5 and stained with AnnexinV-PI;
  • Figure 6 shows the results of HEL-resistant model cells treated with regorafenib in Example 6, and cell proliferation detected by CellTiter-LumiTM luminescence method
  • Fig. 7 shows the result of flow detection of apoptosis of HEL-resistant model cells treated with regorafenib in Example 7 and stained with Annexin V-PI;
  • Figure 8 shows the results of regorafenib treatment of PV cell lines in Example 8, and cell proliferation detected by CellTiter-Lumi TM luminescence method
  • Fig. 9 shows the results of flow cytometry of apoptosis of PV cell lines treated with regorafenib in Example 9 and stained with Annexin V-PI.
  • the invention discloses new applications of sorafenib, regorafenib and their analogs or derivatives. Those skilled in the art can learn from the content of this document and appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the method and product of the present invention have been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods described herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention. Invention technology.
  • the reagents involved in the examples of the present invention are all commercially available products, which can be purchased through commercial channels.
  • Example 1 Establishment of two common drug-resistant cell models (HEL PE , HEL RE ).
  • HEL Human erythroleukemia cell line
  • drug-resistant HEL cells were cultured in RPMI medium (Gibco) containing 20% heat-inactivated fetal bovine serum (Gibco) and 1% penicillin/streptomycin (Gibco).
  • the HEL PE model the HEL-persistent model, was constructed by treating HEL blast cells with a high concentration of ruxolitinib that exceeded the IC50 concentration of blast cells by more than 100 times.
  • the concentration we used was 2.0 ⁇ M. Change the medium every two days, the cells that cannot tolerate it die quickly, and the expanded cells are DTP (drug-tolerant-persisters), and this cell subset is difficult to be killed by antitumor drugs. Stable resistant cells were obtained after 4-6 weeks.
  • Another drug resistance model is HEL RE , the HEL-resistant model.
  • the construction method is to start dosing at a concentration lower than the IC50 of the original cell, and slowly increase it to a high concentration to keep the cells from being killed. Our starting concentration is 0.1 ⁇ M, and the drug is added when the cells proliferate, and the dosing gradient is 1.25 times increasing, and the final concentration is 2.0 ⁇ M. Stable resistant cells were obtained after 4-6 weeks.
  • Ruxolitinib, sorafenib and regorafenib are all from Selleck or Bayer, dissolved in DMSO, the concentration of the stock solution is 10 mM, frozen at -80 °C, and the working solution is diluted with RPMI medium to the specified times before processing cells .
  • Sorafenib is specifically sorafenib mesylate.
  • the above cell lines were cultured in a system of 3000 cells/200 ⁇ L per well, adding increasing concentrations of the inhibitor (concentration gradient: 0, 1, 2.5, 5, 10, 20 ⁇ M), supplemented by DMSO to the same amount.
  • Concentration gradient: 0, 1, 2.5, 5, 10, 20 ⁇ M concentration gradient: 0, 1, 2.5, 5, 10, 20 ⁇ M
  • Multi-plate reader reading, IC50 calculated by GraphPadprism.
  • cell proliferation rate (Luminescence value of drug-added group-average Luminescence value of blank well)/(Luminescence value of DMSO control group-average Luminescence value of blank well) ⁇ 100%.
  • the method to evaluate whether the model is successfully constructed is to compare the IC50 of drug-resistant cells and naive cells, and the ratio is the drug-resistance index.
  • the IC50 of HEL cells is 0.050 (0.002-1.24) ⁇ M
  • the IC50 of HEL PE is 25.5 (137-47.5) ⁇ M
  • the drug resistance index is 510, which indicates the successful construction of the HEL-persistent model
  • b is the IC50 of HEL RE. It was 24.9 (15.6-39.7) ⁇ M, and its drug resistance index was 498, indicating the successful construction of the HEL-resistant model.
  • the results of the growth rate in the figure are shown as the mean ⁇ standard deviation, and the IC50 is shown as the mean. Results are shown as means (95% confidence interval) in the analysis.
  • the method is to treat the drug-resistant cell lines with increasing concentrations of sorafenib, and detect the cell proliferation by CellTiter-Lumi TM luminescence method.
  • the method is the same as that in Example 1, and the results are shown in FIG.
  • Figure 2a reflects that in the ruxolitinib-resistant cell model HEL-persistent, the IC50 value of sorafenib is 2.80 ⁇ M, which is 1/9 of the IC50 value of ruxolitinib of 25.5 ⁇ M, and Figure 2b reflects In the ruxolitinib-resistant cell model HEL-resistant, the IC50 value of sorafenib was 3.56 ⁇ M, which was 1/7 of the ruxolitinib IC50 value of 24.9 ⁇ M. This indicated that sorafenib could inhibit the proliferation of ruxolitinib-resistant cells, and this effect was enhanced with increasing concentration.
  • Sorafenib can promote the apoptosis of two drug-resistant cell lines
  • the drug-resistant cell lines were treated with increasing concentrations of sorafenib for 24 hours (concentrations: 0, 2.5, 5, 10 ⁇ M), and DMSO was supplemented to an equal amount. Three parallel replicate groups were set up, and the apoptosis of cells was detected by flow cytometry after AnnexinV-PI staining.
  • the apoptosis rate the ratio of early apoptotic cells (Annexin V+/PI-) + the ratio of late apoptotic cells and necrotic cells (Annexin V+/PI+).
  • the drug concentrations (average apoptosis rate) of the ruxolitinib treatment group were: 0 ⁇ M (0.91%), 2.5 ⁇ M (0.920%), 5 ⁇ M (1.11%), 10 ⁇ M (0.740%); Sorafenib treatment
  • the drug concentration (apoptosis rate) in the group was 0 ⁇ M (0.910%), 2.5 ⁇ M (2.16%), 5 ⁇ M (11.1%) and 10 ⁇ M (18.0%).
  • the drug concentration (apoptosis rate) of the ruxolitinib treatment group was 0 ⁇ M (0.760%), 2.5 ⁇ M (1.16%), 5 ⁇ M (1.35%), and 10 ⁇ M (1.05%); the sorafenib treatment group
  • the drug concentrations (average apoptosis rate) were 0 ⁇ M (0.760%), 2.5 ⁇ M (1.22%), 5 ⁇ M (5.58%), and 10 ⁇ M (18.6%). This suggests that sorafenib can promote apoptosis in HEL PE/RE model, and this effect increases with increasing concentration.
  • the method is to treat the original cell line with increasing concentrations of sorafenib, and detect the cell proliferation by CellTiter-Lumi TM luminescence method.
  • the method is the same as in Example 1, and the results are shown in Figure 4.
  • the drug concentrations (average rate of increase) in the ruxolitinib treatment group in Figure 4 are: 0 ⁇ M (100%), 1 ⁇ M (41.4%), 2.5 ⁇ M (40.6%), 5 ⁇ M (42.8%), 10 ⁇ M (40.8%), 20 ⁇ M (22.9%); Sorafenib treatment group drug concentration (mean rate of increase): 0 ⁇ M (100%), 1 ⁇ M (80.3%), 2.5 ⁇ M (72.1%), 5 ⁇ M (40.0%), 10 ⁇ M (6.35%) , 20 ⁇ M (0.828%).
  • sorafenib can inhibit the proliferation of human PV cell line-HEL cells, and the effect increases with the increase of drug concentration, and the inhibitory effect is better than that of ruxolitinib at the concentration of 5 ⁇ M and above.
  • Sorafenib can promote apoptosis of PV cell lines
  • the drug concentrations (average apoptosis rate) in the ruxolitinib treatment group in Figure 5 are: 0 ⁇ M (2.88%), 2.5 ⁇ M (4.65%), 5 ⁇ M (5.07%), and 10 ⁇ M (4.59%); the sorafenib treatment group
  • the drug concentration (apoptosis rate) was 0 ⁇ M (2.88%), 2.5 ⁇ M (5.82%), 5 ⁇ M (10.9%), and 10 ⁇ M (16.1%). This indicates that sorafenib can promote the apoptosis of human PV cell line-HEL cells, and the effect increases with the increase of drug concentration, and the pro-apoptotic effect of 2.5 ⁇ M and above is better than that of ruxolitinib.
  • Figure 6 reflects that in the ruxolitinib-resistant cell model HEL-resistant, the IC50 value of regorafenib was 0.514 ⁇ M, which was 1/290 of the ruxolitinib IC50 value of 149 ⁇ M. This indicates that regorafenib can inhibit the proliferation of ruxolitinib-resistant cells, and this effect is enhanced with the increase of concentration.
  • the drug concentrations (average apoptosis rate) of ruxolitinib treatment group in Figure 7 are: 0 ⁇ M (2.51%), 2.5 ⁇ M (3.75%), 5 ⁇ M (3.70%), 10 ⁇ M (4.34%); regorafenib treatment group
  • the drug concentration (apoptosis rate) was 0 ⁇ M (2.51%), 2.5 ⁇ M (9.50%), 5 ⁇ M (12.9%), and 10 ⁇ M (14.7%). This indicated that regorafenib could promote the apoptosis of ruxolitinib-resistant cells, and the effect increased with the increase of drug concentration.
  • Example 8 Regorafenib inhibits the proliferation of PV cell lines.
  • the method is to treat the original cell line with increasing concentrations of regorafenib, and detect the cell proliferation by CellTiter-Lumi TM luminescence method.
  • the method is the same as that in Example 1, and the results are shown in Figure 8.
  • the drug concentrations (average rate of increase) in the ruxolitinib treatment group in Figure 4 are: 0 ⁇ M (100%), 1 ⁇ M (50.5%), 2.5 ⁇ M (48.4%), 5 ⁇ M (50.2%), 10 ⁇ M (48.4%), 20 ⁇ M (28.5%); drug concentrations (mean rate of increase) in the regorafenib treatment group were: 0 ⁇ M (100%), 1 ⁇ M (84.7%), 2.5 ⁇ M (57.7%), 5 ⁇ M (32.1%), 10 ⁇ M (17.7%) , 20 ⁇ M (1.15%). This suggests that regorafenib can inhibit the proliferation of human PV cell line-HEL cells, and the effect increases with the increase of drug concentration.
  • the drug concentrations (average apoptosis rate) of ruxolitinib treatment group in Figure 5 are: 0 ⁇ M (0.965%), 2.5 ⁇ M (2.05%), 5 ⁇ M (2.14%), 10 ⁇ M (2.16%); regorafenib treatment group
  • the drug concentration (apoptosis rate) was 0 ⁇ M (0.965%), 2.5 ⁇ M (4.31%), 5 ⁇ M (7.76%), and 10 ⁇ M (10.6%). This indicates that regorafenib can promote the apoptosis of human PV cell line-HEL cells, and the effect increases with the increase of drug concentration.

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Abstract

索拉非尼或瑞戈替尼或它们的类似物或衍生物在制备治疗骨髓增殖性肿瘤的药物中的应用。所述骨髓增殖性肿瘤为真性红细胞增多症或具有耐药性的骨髓增殖性肿瘤。

Description

索拉非尼、瑞戈非尼及其类似物或衍生物的新应用
本申请要求于2020年07月13日提交中国专利局、申请号为202010668274.3、发明名称为“索拉菲尼、瑞戈非尼及其类似物或衍生物的新应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药技术领域，具体涉及索拉非尼、瑞戈非尼及其类似物或衍生物的新应用，尤其是索拉非尼、瑞戈非尼及其类似物或衍生物在制备治疗真性红细胞增多症及芦可替尼耐药性的骨髓增殖性肿瘤的药物中的应用。
背景技术
骨髓增殖性肿瘤(Myeloproliferative neoplasmas，MPNs)是指分化相对成熟的一系或多系骨髓细胞克隆性增殖所致的一组肿瘤性疾病。2016年世界卫生组织(WHO)骨髓肿瘤分类修订包括以下骨髓增生性肿瘤(MPNs):慢性粒细胞白血病(chronic myeloid leukemia，CML)，BCR-ABL 1+；慢性中性粒细胞白血病(chronic neutrophilic leukemia)；真性红细胞增多症(polycythemiavera,PV)；原发性骨髓纤维化(primary myelofibrosis，PMF)；原发性血小板增多症(essentialthrombocythemia，ET)；慢性嗜酸性白血病，未另作说明(chronic eosinophilic leukemia，not otherwise specified)；和MPN不可归类(MPN,unclassifiable)。PV、ET和PMF被归入费城阴性经典MPN(Philadelphia-negative classical MPNs)的范畴，在临床表现为一种或多种血细胞增生，伴肝、脾或淋巴结肿大。MPNS为克隆性造血干细胞疾病，主要的驱动疾病的基因突变包括JAK2/V617F、CALR、MPL突变，其中JAK2/V617F突变是最常见的类型，可见于95％的PV、50-60％的ET和55-65％的PMF患者。大约3％的PV患者中可发现JAK2外显子12中有插入或缺失突变。
PV和ET患者的治疗目标是避免血栓性和出血并发症。PMF治疗的主 要目标是延长生存期，若条件允许，尽可能通过异体干细胞移植(Allogeneic stem-cell transplantation，AlloSCT)来达到治愈的目的；如果不能延长生存期或治愈，治疗的主要目标改为缓解症状和改善生活质量。目前临床上根据“2016年世界卫生组织对髓样肿瘤和急性白血病分类”的标准诊断MPNs，进行危险度分层并采取相应的治疗措施。
芦可替尼(Ruxolitinib，RUX)，作为JAK1/JAK2抑制剂，被FDA批准一线用于对中、高危骨髓纤维化(myelofibrosis,MF)包括原发性骨髓纤维化、真性红细胞增多症后骨髓纤维化和原发性血小板增多症后骨髓纤维化。并作为二线药物用于羟基脲(Hydroxyurea，HU)耐药或不能耐受的PV患者。二期、三期临床试验结果提示，与最佳疗法(best available therapy，BAT)相比，RUX能够减少中、高危MF和PV患者的脾脏体积和减轻症状。HU不能耐受和耐药的ET患者接受RUX治疗未见任何效果。COMFORT和RESPONSE临床试验结果显示，RUX治疗MF和PV患者时，贫血和血小板减少是剂量依赖性的毒副作用。接受RUX治疗的MF患者贫血更重，有51％的患者需要至少一次的红细胞输注，约5％的患者因这个原因而中断治疗。此外，长时间使用RUX等I型JAK抑制剂可诱导耐药的发生，在临床研究中也发现了几种I型JAK抑制剂之间的交叉耐药。I型JAK抑制剂不能显著减少突变等位基因负荷，因此其治疗潜力有限。总的来说，RUX作为I型JAK2抑制剂，代表了治疗MPNs的一个重要进展，但它并没有达到很高的期望。BMS911543作为一种更具JAK2选择性的抑制剂，已完成了I/II期研究(NCT01236352)，而其他具有JAK2/FLT3抑制谱的化合物(fedratinib，pacritinib)由于不良事件的发生没有完成III期研究。
骨髓移植是唯一治愈MPNs的方法，但是仍然有一些问题需要解决。移植方式和方案的选择还不确定，选择同种异体移植还是单倍体同种移植尚不清楚。此外，当选择移植时，必须考虑到移植相关死亡率和骨髓增殖性肿瘤的长期性。目前骨髓移植主要用于治疗高危的骨髓纤维化患者，但其他类型的MPNs患者选择骨髓移植的时机需要进一步探讨和研究证实。骨髓移植费用昂贵，在目前的医疗环境下，对大多数患者来说无法选择该治疗手段。
总之，芦可替尼是MPNs治疗的里程碑药物，但病人对其产生耐药后缺乏好的治疗药物是目前MPN治疗中的重大挑战。而目前没有任何可用的针对芦可替尼耐药病人的药物。
发明内容
有鉴于此，本发明的目的在于针对现有技术存在的问题，提供一种针对骨髓增殖性肿瘤尤其是针对芦可替尼耐药病人的药物。
索拉非尼(Sorafenib)是在广泛的肿瘤模型中抑制肿瘤细胞增殖、血管生成和增加凋亡的小分子化合物。它作为一种口服受体酪氨酸激酶抑制剂，可抑制与肿瘤发生和肿瘤进展有关的因子，如Raf丝氨酸/苏氨酸激酶和受体酪氨酸激酶(血管内皮生长因子受体1、2、3和血小板衍生生长因子-β、Flt-3和c-kit)。索拉非尼被美国FDA批准用于治疗晚期不可手术的肝癌(hepatocellular carcinoma,HCC)和晚期肾细胞癌(renal cell carcinoma,RCC)，以及晚期放射性碘难治性分化的甲状腺癌(radioiodine-referectory differentiated thyroid cancer,RRDTC)。索拉非尼分子式为C 21H 16ClF 3N 4O 3，分子量464.83，结构式如式I所示。
Figure PCTCN2021102607-appb-000001
索拉非尼类似物瑞戈非尼(Regorafenib)分子式为C 21H 15ClF 4N 4O 3， 分子量482.82，结构式如式II所示。
Figure PCTCN2021102607-appb-000002
在本发明中，通过细胞系模型来明确索拉非尼对骨髓增殖性肿瘤细胞(耐药与非耐药)的抑制作用。
在一些实施方案中，本发明基于HEL细胞(Human erythroleukemia cell line)这种常用的含JAK2-V617F突变的人源骨髓增殖性肿瘤细胞系，建立了两种常见耐药细胞模型HEL PE和HEL RE。HEL PE模型即HEL-persistent模型，构建方法为使用超过
Figure PCTCN2021102607-appb-000003
细胞IC50浓度100倍以上的高浓度芦可替尼处理
Figure PCTCN2021102607-appb-000004
细胞，每两天换一次液，不能耐受的细胞很快死亡，扩增起来的细胞为DTP(drug-tolerant-persisters)，这种细胞亚群难以被抗肿瘤药物杀灭。另外一种耐药模型为HEL RE即HEL-resistant模型，构建方法为使用低于
Figure PCTCN2021102607-appb-000005
细胞IC50浓度开始加药，缓慢递增至高浓度，维持细胞不被杀灭。
在一些实施方案中，本发明使用递增浓度的索拉非尼处理两种耐药细胞株，通过CellTiter-Lumi TM发光法检测细胞的增殖。结果显示，索拉非尼可成功抑制HEL PE模型和HEL RE模型的细胞的增殖。
在一些实施方案中，本发明使用递增浓度的索拉非尼处理两种耐药细胞株，使用AnnexinV-PI染色后流式检测细胞的凋亡情况。结果显示，索拉非尼可促进HEL PE模型和HEL RE模型的细胞的凋亡。
在一些实施方案中，本发明使用递增浓度的瑞戈非尼(索拉非尼类似物)处理HEL RE耐药细胞株，通过CellTiter-Lumi TM发光法检测细胞的增殖，同时使用AnnexinV-PI染色后流式检测细胞的凋亡情况。结果显示，瑞戈非尼可成功抑制HEL RE模型的细胞的增殖，促进HEL RE模型的细胞的凋亡。
由此可见，索拉非尼、瑞戈非尼及其类似物或衍生物可用于治疗芦可替尼耐药的MPN疾病。
进一步的，在一些实施方案中，本发明使用递增浓度的索拉非尼、瑞戈非尼及其类似物或衍生物处理研究PV常用的人源细胞模型HEL，通过CellTiter-Lumi TM发光法检测细胞的增殖。结果显示，索拉非尼、瑞戈非尼及其类似物或衍生物可成功抑制HEL细胞的增殖。因此本发明提供了索拉非尼、瑞戈非尼及其类似物或衍生物在制备抑制HEL细胞的增殖的药物中的应用。
在一些实施方案中，本发明使用递增浓度的索拉非尼、瑞戈非尼及其类似物或衍生物处理研究PV常用的人源细胞模型HEL，使用AnnexinV-PI染色后流式检测细胞的凋亡情况。结果显示，索拉非尼、瑞戈非尼及其类似物或衍生物可促进HEL细胞的凋亡。因此本发明提供了索拉非尼、瑞戈非尼及其类似物或衍生物在制备促进HEL细胞的凋亡的药物中的应用。
由此可见，索拉非尼、瑞戈非尼及其类似物或衍生物可通过抑制HEL细胞的增殖、促进HEL细胞凋亡，用于治疗骨髓增殖性肿瘤，尤其是真性红细胞增多症。
综上所述，本发明提供了索拉非尼、瑞戈非尼及其类似物或衍生物在制备治疗骨髓增殖性肿瘤的药物中的应用。
进一步的，所述骨髓增殖性肿瘤为真性红细胞增多症或具有耐药性的骨髓增殖性肿瘤。
在一些实施方案中，所述具有耐药性的骨髓增殖性肿瘤为芦可替尼耐 药性的骨髓增殖性肿瘤。
在一些实施方案中，所述具有耐药性的骨髓增殖性肿瘤为具有耐药性的真性红细胞增多症、具有耐药性的原发性骨髓纤维化以及具有耐药性的原发性血小板增多症。
其中，所述药物包括索拉非尼、瑞戈非尼及其类似物或衍生物。
所述药物包括索拉非尼的类似物：瑞戈非尼(Regorafenib)，瑞戈非尼与索拉非尼的区别在于，索拉非尼中的一个H在瑞戈非尼中变成了F。瑞戈非尼是一种口服酪氨酸激酶抑制剂，被批准用于治疗难治性转移性结直肠癌、之前使用伊马替尼和舒尼替尼治疗的晚期胃肠道间质瘤，以及使用索拉非尼后进展的不可切除肝癌。
在本发明的一些具体实施方案中，使用的索拉非尼具体为甲磺酸索拉非尼。
进一步的，所述药物还包括药学上可接受的辅料。
所述药物可以为当前药品领域任何剂型，包括口服制剂或注射制剂。
各药物剂型可根据该剂型实际需要选取合适的可接受辅料来制备，这属于本领域常规的剂型制备技术。如制成胶囊剂、片剂、注射粉剂等。
由上述技术方案可知，本发明提供了索拉非尼、瑞戈非尼及其类似物或衍生物在制备治疗骨髓增殖性肿瘤的药物中的应用。所述骨髓增殖性肿瘤为真性红细胞增多症或芦可替尼耐药性的骨髓增殖性肿瘤。索拉非尼、瑞戈非尼及其类似物或衍生物用于真性红细胞增多症的治疗给广大真性红细胞增多症的患者提供了新的治疗途径，给临床医生及患者提供了更多选择。对于芦可替尼耐药的骨髓增殖性肿瘤患者，索拉非尼、瑞戈非尼及其类似物或衍生物能为患者提供继续的口服药物治疗，免于接受骨髓移植。索拉非尼、瑞戈非尼及其类似物或衍生物可以化学合成，成本较生物制剂要低。且已经通过FDA及NMPA的批准上市，用于临床治疗。其副反应较少较轻，临床病人耐受性良好，且病人负担较轻。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对 实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示实施例1耐药细胞模型HEL PE和HEL RE的建立结果图；a为HEL-persistent模型成功构建；b为HEL-resistant模型的成功构建；
图2示实施例2索拉非尼处理两种耐药细胞株，通过CellTiter-Lumi TM发光法检测细胞增殖的结果图；a为HEL-persistent模型细胞增殖结果图；b为HEL-resistant模型细胞增殖结果图；
图3示实施例3索拉非尼处理两种耐药细胞株，使用AnnexinV-PI染色后流式检测细胞凋亡的结果图；a为HEL-persistent模型细胞凋亡结果图；b为HEL-resistant模型细胞凋亡结果图；
图4示实施例4索拉非尼处理PV细胞系，通过CellTiter-Lumi TM发光法检测细胞增殖的结果图；
图5示实施例5索拉非尼处理PV细胞系，使用AnnexinV-PI染色后流式检测细胞凋亡的结果图；
图6示实施例6瑞戈非尼处理HEL-resistant模型细胞，通过CellTiter-Lumi TM发光法检测细胞增殖的结果图；
图7示实施例7瑞戈非尼处理HEL-resistant模型细胞，使用Annexin V-PI染色后流式检测细胞凋亡的结果图；
图8示实施例8瑞戈非尼处理PV细胞系，通过CellTiter-Lumi TM发光法检测细胞增殖的结果图；
图9示实施例9瑞戈非尼处理PV细胞系，使用AnnexinV-PI染色后流式检测细胞凋亡的结果图。
具体实施方式
本发明公开了索拉非尼、瑞戈非尼及其类似物或衍生物的新应用。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及产品已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的 方法进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
如无特殊说明，本发明实施例中所涉及的试剂均为市售产品，均可以通过商业渠道购买获得。
实施例1、两种常见耐药细胞模型的建立(HEL PE，HEL RE)。
一、材料与方法
1、细胞系
HEL(Human erythroleukemia cell line)以及耐药的HEL细胞均培养于含20％热灭活胎牛血清(Gibco)及1％青霉素/链霉素(Gibco)的RPMI培养基(Gibco)。
HEL PE模型即HEL-persistent模型，构建方法为使用超过原始细胞IC50浓度100倍以上的高浓度芦可替尼处理HEL原始细胞，我们使用的浓度为2.0μM。每两天换一次液，不能耐受的细胞很快死亡，扩增起来的细胞为DTP(drug-tolerant-persisters)，这种细胞亚群难以被抗肿瘤药物杀灭。4-6周后获得稳定的耐药细胞。另外一种耐药模型为HEL RE即HEL-resistant模型，构建方法为使用低于原始细胞IC50浓度开始加药，缓慢递增至高浓度，维持细胞不被杀灭。我们的起始浓度为0.1μM，细胞出现增殖就加药，加药梯度为成1.25倍递增，终浓度为2.0μM。4-6周后获得稳定的耐药细胞。
2、抑制剂
芦可替尼、索拉非尼以及瑞戈非尼均来自Selleck或拜耳公司，溶于DMSO，母液浓度为10mM，冻存于-80℃，工作液采用RPMI培养基稀释至指定倍数后处理细胞。索拉非尼具体为甲磺酸索拉非尼。
3、体外抑制试验
为了检测抑制剂的抗增殖效应，上述细胞系以每孔3000个细胞/200 μL体系培养，加入递增浓度的抑制剂(浓度梯度：0，1，2.5，5，10，20μM)，DMSO补齐至等量。设4个平行重复组，并设3个空白孔(不含细胞的培养液孔)。72小时后通过CellTiter-Lumi TM发光法(碧云天)检测细胞的增殖。多功能酶标仪读数，IC50通过GraphPadprism计算得来。
细胞增值率计算公式：细胞增殖率＝(加药组Luminescence值-空白孔平均Luminescence值)/(DMSO对照组Luminescence值-空白孔平均Luminescence值)×100％。
评价模型是否构建成功的方法是比较耐药细胞与幼稚细胞的IC50，比值为耐药指数，大于3即为构建成功。
二、结果分析
图1中a图HEL细胞IC50为0.050(0.002-1.24)μM,HEL PE IC50为25.5(137-47.5)μM，其耐药指数为510，提示HEL-persistent模型的成功构建，b图HEL REIC50为24.9(15.6-39.7)μM，其耐药指数为498，提示HEL-resistant模型的成功构建。图中增值率结果显示为平均数±标准差，IC50显示为均数。结果分析中显示为均数(95％可信区间)。
实施例2、索拉非尼可抑制两种耐药细胞株的增殖
方法为使用递增浓度的索拉非尼处理耐药细胞株，通过CellTiter-Lumi TM发光法检测细胞的增殖，方法同实施例1，结果见图2。
结果显示，图2a反映了在芦可替尼耐药细胞模型HEL-persistent中，索拉非尼的IC50值为2.80μM，为芦可替尼IC50值25.5μM的1/9，图2b反映了在芦可替尼耐药细胞模型HEL-resistant中，索拉非尼的IC50值为3.56μM，为芦可替尼IC50值24.9μM的1/7。这说明索拉非尼可抑制芦可替尼耐药细胞的增殖，这种效应表现为随浓度的升高而增强。
实施例3、索拉非尼可促进两种耐药细胞株的凋亡
一、材料与方法
1、细胞系与抑制剂同实施例1。
2、细胞凋亡检测
为了检测抑制剂的促凋亡效应，使用递增浓度的索拉非尼处理耐药细胞株24小时(浓度：0、2.5、5、10μM)，补齐DMSO至等量。设3个平行重复组，使用AnnexinV-PI染色后流式检测细胞的凋亡情况。
细胞凋亡率计算公式：细胞凋亡率＝早期凋亡细胞比率(Annexin V+/PI-)+晚期凋亡细胞及坏死细胞比率(AnnexinV+/PI+)。
二、结果分析
图3a中，芦可替尼处理组药物浓度(平均凋亡率)为：0μM(0.91％)、2.5μM(0.920％)、5μM(1.11％)、10μM(0.740％)；索拉非尼处理组药物浓度(凋亡率)为0μM(0.910％)、2.5μM(2.16％)、5μM(11.1％)、10μM(18.0％)。；图3b中，芦可替尼处理组药物浓度(凋亡率)为0μM(0.760％)、2.5μM(1.16％)、5μM(1.35％)、10μM(1.05％)；索拉非尼处理组药物浓度(平均凋亡率)为0μM(0.760％)、2.5μM(1.22％)、5μM(5.58％)、10μM(18.6％)。这提示索拉非尼能促进HEL PE/RE模型的凋亡，这种效应随浓度的上升而增强。
实施例4、索拉非尼可抑制PV细胞系的增殖。
方法为使用递增浓度的索拉非尼处理原始细胞株，通过CellTiter-Lumi TM发光法检测细胞的增殖。方法同实施例1，结果见图4。
图4中芦可替尼处理组药物浓度(平均增值率)为：0μM(100％)、1μM(41.4％)、2.5μM(40.6％)、5μM(42.8％)、10μM(40.8％)、20μM(22.9％)；索拉非尼处理组药物浓度(平均增值率)为：0μM(100％)、1μM(80.3％)、2.5μM(72.1％)、5μM(40.0％)、10μM(6.35％)、20μM(0.828％)。这提示索拉非尼可抑制人源PV细胞系-HEL细胞的增殖，该效应随药物浓度增加而增加，在5μM及以上浓度抑制效果优于芦可替尼。
实施例5、索拉非尼可促进PV细胞系的凋亡
方法为使用递增浓度的索拉非尼处理原始细胞株，使用AnnexinV-PI染色后流式检测细胞的凋亡情况。方法同实施例3，结果见图5。
图5中芦可替尼处理组药物浓度(平均凋亡率)为：0μM(2.88％)、2.5μM(4.65％)、5μM(5.07％)、10μM(4.59％)；索拉非尼处理组药物浓度(凋亡率)为0μM(2.88％)、2.5μM(5.82％)、5μM(10.9％)、10μM(16.1％)。这说明索拉非尼可促进人源PV细胞系——HEL细胞的的凋亡，该效应随药物浓度的增加而增加，在2.5μM及以上浓度促凋亡效果优于芦可替尼。
实施例6、瑞戈非尼可抑制HEL-resistant细胞的增殖。
方法为使用递增浓度的瑞戈非尼处理耐药细胞株，通过CellTiter-Lumi TM发光法检测细胞的增殖。方法同实施例1，结果见图6。
图6反映了在芦可替尼耐药细胞模型HEL-resistant中，瑞戈非尼的IC50值为0.514μM，为芦可替尼IC50值149μM的1/290。这说明瑞戈非尼可抑制芦可替尼耐药细胞的增殖，这种效应表现为随浓度的升高而增强。
实施例7、瑞戈非尼可促进HEL-resistant细胞的凋亡
方法为使用递增浓度的瑞戈非尼处理耐药细胞株，使用AnnexinV-PI染色后流式检测细胞的凋亡情况。方法同实施例3，结果见图7。
图7中芦可替尼处理组药物浓度(平均凋亡率)为：0μM(2.51％)、2.5μM(3.75％)、5μM(3.70％)、10μM(4.34％)；瑞戈非尼处理组药物浓度(凋亡率)为0μM(2.51％)、2.5μM(9.50％)、5μM(12.9％)、10μM(14.7％)。这说明瑞戈非尼可促进芦可替尼耐药细胞的凋亡，该效应随药物浓度的增加而增加。
实施例8、瑞戈非尼可抑制PV细胞系的增殖。
方法为使用递增浓度的瑞戈非尼处理原始细胞株，通过CellTiter-Lumi TM发光法检测细胞的增殖。方法同实施例1，结果见图8。
图4中芦可替尼处理组药物浓度(平均增值率)为：0μM(100％)、1μM(50.5％)、2.5μM(48.4％)、5μM(50.2％)、10μM(48.4％)、20μM(28.5％)；瑞戈非尼处理组药物浓度(平均增值率)为：0μM(100％)、1μM(84.7％)、 2.5μM(57.7％)、5μM(32.1％)、10μM(17.7％)、20μM(1.15％)。这提示瑞戈非尼可抑制人源PV细胞系-HEL细胞的增殖，该效应随药物浓度增加而增加。
实施例9、瑞戈非尼可促进PV细胞系的凋亡
方法为使用递增浓度的瑞戈非尼处理原始细胞株，使用AnnexinV-PI染色后流式检测细胞的凋亡情况。方法同实施例3，结果见图9。
图5中芦可替尼处理组药物浓度(平均凋亡率)为：0μM(0.965％)、2.5μM(2.05％)、5μM(2.14％)、10μM(2.16％)；瑞戈非尼处理组药物浓度(凋亡率)为0μM(0.965％)、2.5μM(4.31％)、5μM(7.76％)、10μM(10.6％)。这说明瑞戈非尼可促进人源PV细胞系-HEL细胞的的凋亡，该效应随药物浓度的增加而增加。
以上对本发明所提供的索拉非尼、瑞戈非尼及其类似物或衍生物的新应用进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (8)

  1. 索拉非尼、瑞戈非尼及其类似物或衍生物在制备治疗骨髓增殖性肿瘤的药物中的应用。
  2. 根据权利要求1所述的应用，所述骨髓增殖性肿瘤为真性红细胞增多症或具有耐药性的骨髓增殖性肿瘤。
  3. 根据权利要求2所述的应用，所述具有耐药性的骨髓增殖性肿瘤为芦可替尼耐药性的骨髓增殖性肿瘤。
  4. 根据权利要求2所述的应用，所述具有耐药性的骨髓增殖性肿瘤为具有耐药性的真性红细胞增多症、具有耐药性的原发性骨髓纤维化以及具有耐药性的原发性血小板增多症。
  5. 索拉非尼、瑞戈非尼及其类似物或衍生物在制备抑制HEL细胞的增殖的药物中的应用。
  6. 索拉非尼、瑞戈非尼及其类似物或衍生物在制备促进HEL细胞的凋亡的药物中的应用。
  7. 根据权利要求1-6任一项所述的应用，所述药物还包含药学上可接受的辅料。
  8. 根据权利要求1-6任一项所述的应用，所述药物为口服制剂或注射制剂。
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