New applications of sorafenib, regorafenib and their analogs or derivatives

A drug resistance technology, applied in the field of medicine, can solve the problems of high cost of bone marrow transplantation and lack of good therapeutic drugs, and achieve the effect of good tolerance of clinical patients, light side effects and low cost

Active Publication Date: 2022-04-15
THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Bone marrow transplantation is expensive and, in the current medical environment, not an option for most patients
[0006] In short, ruxolitinib is a milestone drug in the treatment of MPNs, but the lack of good therapeutic drugs after patients become resistant to it is a major challenge in the current treatment of MPNs
Currently, there are no available drugs for ruxolitinib-resistant patients

Method used

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  • New applications of sorafenib, regorafenib and their analogs or derivatives
  • New applications of sorafenib, regorafenib and their analogs or derivatives
  • New applications of sorafenib, regorafenib and their analogs or derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1, the establishment of two common drug-resistant cell models (HEL PE , HEL RE ).

[0046] 1. Materials and methods

[0047] 1. Cell line

[0048] HEL (Human erythroleukemia cell line) and drug-resistant HEL cells were cultured in RPMI medium (Gibco) containing 20% ​​heat-inactivated fetal bovine serum (Gibco) and 1% penicillin / streptomycin (Gibco).

[0049] HEL PE The model is the HEL-persistent model, which is constructed by treating HEL primitive cells with a high concentration of ruxolitinib that exceeds the IC50 concentration of the primitive cells by 100 times, and the concentration we use is 2.0 μM. The solution was changed every two days, and the cells that could not tolerate it died quickly, and the amplified cells were DTP (drug-tolerant-persisters), which were difficult to be killed by anti-tumor drugs. Stable drug-resistant cells were obtained after 4-6 weeks. Another resistance model is HEL RE That is, the HEL-resistant model, the construc...

Embodiment 2

[0058] Example 2, Sorafenib can inhibit the proliferation of two drug-resistant cell lines

[0059] The method is to use increasing concentrations of Sorafenib to treat drug-resistant cell lines, through CellTiter-Lumi TM Luminescence method is used to detect the proliferation of cells, the method is the same as in Example 1, and the results are shown in figure 2 .

[0060] The results show, figure 2 a reflects that in the ruxolitinib-resistant cell model HEL-persistent, the IC50 value of sorafenib is 2.80 μM, which is 1 / 9 of the ruxolitinib IC50 value of 25.5 μM, figure 2b reflects that in the ruxolitinib-resistant cell model HEL-resistant, the IC50 value of sorafenib is 3.56 μM, which is 1 / 7 of the ruxolitinib IC50 value of 24.9 μM. This shows that sorafenib can inhibit the proliferation of ruxolitinib-resistant cells, and this effect is enhanced with the increase of concentration.

Embodiment 3

[0061] Example 3, Sorafenib can promote the apoptosis of two drug-resistant cell lines

[0062] 1. Materials and methods

[0063] 1. Cell lines and inhibitors are the same as in Example 1.

[0064] 2. Apoptosis detection

[0065] In order to detect the pro-apoptotic effect of the inhibitor, the drug-resistant cell line was treated with increasing concentrations of Sorafenib for 24 hours (concentration: 0, 2.5, 5, 10 μM), and DMSO was supplemented to the same amount. Three parallel repeat groups were set up, and the apoptosis of cells was detected by flow cytometry after AnnexinV-PI staining.

[0066] Apoptotic rate calculation formula: Apoptotic rate = ratio of early apoptotic cells (AnnexinV+ / PI-) + ratio of late apoptotic cells and necrotic cells (AnnexinV+ / PI+).

[0067] 2. Results analysis

[0068] image 3 In a, the drug concentration (average apoptosis rate) of ruxolitinib treatment group is: 0 μM (0.91%), 2.5 μM (0.920%), 5 μM (1.11%), 10 μM (0.740%); Sorafenib tre...

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Abstract

The application belongs to the field of medical technology, and discloses a new application specifically related to sorafenib, especially the application of sorafenib in the preparation of drugs for treating myeloproliferative tumors. The myeloproliferative neoplasm is polycythemia vera or ruxolitinib-resistant myeloproliferative neoplasm. The use of sorafenib 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. For patients with ruxolitinib-resistant myeloproliferative neoplasms, sorafenib can provide patients with continued oral drug therapy and avoid bone marrow transplantation. Sorafenib can be chemically synthesized at a lower cost than biological agents. And it has been approved by FDA and NMPA for clinical treatment. Its side effects are less and milder, the clinical patient tolerance is good, and the patient burden is lighter.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to new applications of sorafenib, regorafenib and their analogs or derivatives, especially sorafenib, regorafenib and their analogs or derivatives in the preparation of therapeutic Drug use in polycythemia vera and ruxolitinib-resistant myeloproliferative neoplasms. Background technique [0002] Myeloproliferative neoplasms (MPNs) refer to a group of neoplastic diseases caused by the clonal proliferation of one or more lines of myeloid cells with relatively mature differentiation. The 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms includes the following myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), BCR-ABL 1+ ; chronic neutrophilic leukemia (chronic neutrophilic leukemia); polycythemia vera (PV); primary myelofibrosis (primary myelofibrosis, PMF); essential thrombocythemia (essential thrombocythemia, ET); ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/44A61P35/00
CPCA61K31/44A61P35/00
Inventor 邓沱胡婉钰吾甫尔·艾尼
Owner THE SECOND XIANGYA HOSPITAL OF CENT SOUTH UNIV
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