CN114588269B - Bcl-2 inhibitor and HDAC inhibitor composition and application thereof - Google Patents
Bcl-2 inhibitor and HDAC inhibitor composition and application thereof Download PDFInfo
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The present invention relates to a pharmaceutical composition comprising a Bcl-2 inhibitor and an HDAC inhibitor, wherein the Bcl-2 inhibitor and the HDAC inhibitor produce a synergistic effect. The pharmaceutical composition provides a safe and effective cancer treatment scheme for improving the clinical prognosis of AML patients, in particular for elderly patients or patients with basic diseases such as heart and lung and poor tolerance.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a composition of a Bcl-2 inhibitor and an HDAC inhibitor.
Background
Acute myeloid leukemia (acute myeloid leukemia, AML) is a malignant clonal disease that originates from hematopoietic stem cells and has strong heterogeneity, and is characterized in that the primary cells in the bone marrow clonally proliferate, differentiate into mature disorders, affect normal hematopoietic cell growth, and invade multiple organs throughout the body. The total incidence rate of AML in China is 3-4/10 ten thousand, and the death rate accounts for 1.9% of the total cancer death rate. Although hematopoietic stem cell transplantation and the application of novel targeted drugs and the like in recent years improve the prognosis of part of patients, chemotherapy is still the most important treatment means of AML, and the death rate caused by chemotherapy-related complications is high, tumor cell drug resistance is easy to occur, so that treatment is ineffective, about 30% of patients are difficult to obtain complete remission (complete remission, CR), the median survival time is only 3-6 months, 50-80% of AML patients finally relapse after CR, and the remission rate is low again after relapse; in addition, patients with high risk characteristics of karyotype or molecular biology have poorer prognosis. Therefore, how to reduce the toxic side effects associated with treatment and overcome tumor cell resistance is a hotspot and difficulty in current AML treatments.
In recent years, research on new drugs for AML (AML) at home and abroad is on the way of developing targeting drugs, i.e. IDH1/2 inhibitors and FLT3 inhibitors according to gene mutation, but the drugs have limitations, namely, the drugs can only be used for patients accompanied with corresponding gene mutation, and the single drug treatment effect is poor; epigenetic related drugs, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, etc. have achieved better efficacy in senile AML, but their applicability to the limited population is often limited and combined chemotherapy is needed. Thus, the "3+7" regimen based on anthracyclines and cytarabine remains the first line treatment regimen for AML patients for nearly 30 years. Ara-C belongs to pyrimidine antimetabolites, acts by inhibiting DNA polymerase and causing DNA damage by being doped into an extended DNA chain, is one of very effective medicaments for treating malignant tumors of a blood system, is a basic stone in the current AML induction treatment and consolidation treatment, but old patients often cannot tolerate large doses of Ara-C, and lack of consolidation treatment of large doses of Ara-C, and is one of reasons for bad prognosis of old AML patients. The cytotoxic mechanism of anthracyclines, represented by Daunorubicin (DNR), is the creation of DNA lesions by insertion of DNA and inhibition of topoisomerase II, leading to DNA Double Strand Breaks (DSBs) and induction of apoptosis. Although daunorubicin is most toxic in S phase, the drug is not cycle specific. But the '3+7' scheme has obvious bone marrow suppression, and serious infection, bleeding and other complications related to chemotherapy, and the elderly patients and patients with basic diseases such as heart and lung are poor in tolerance. How to reduce drug toxicity and drug resistance while ensuring therapeutic effects is a challenge for hematology researchers.
CPX-351 approved by the FDA in the United states is a daunorubicin and cytarabine liposome coating compound, so that toxic and side effects are reduced, curative effects are improved, and a new treatment idea is developed for scientific researchers. NL-101 (also called EDO-S101) is also designed based on the principle, is a brand new small molecule compound formed by connecting a DNA damage core group of bendamustine hydrochloride and a histone deacetylase inhibition core group of a histone inhibitor vorinostat (also called SAHA) through covalent bonds, has the action mechanisms of the two medicaments, and can provide a better effect than a single medicament. Researchers found in vitro experiments that NL-101 was able to exert both histone deacetylase inhibitor (HDACi) effects (demonstrated by alpha-tubulin and histone hyperacetylation) and DNA damaging effects (demonstrated by gamma-H2 AX increase) and was more potent than bendamustine alone. Experiments in mice prove that NL-101 has a significantly better curative effect than SAHA and bendamustine single drug. There is a need to explore drugs that are combined with NL-101 in an effort to synergistically inhibit AML with good tolerability.
The occurrence, development and drug resistance of hematological malignancies are highly dependent on the overexpression of the anti-apoptotic protein Bcl-2, bcl-2 being an effective target for anti-tumor therapy, high levels of Bcl-2 expression being closely related to the poor prognosis of AML patients. Venetocelax (ABT-199) is a potent, selective, orally bioavailable small molecule inhibitor of Bcl-2 with a strong affinity for Bcl-2. Venetoclax has strong killing activity on both primary cells and AML cell lines of chronic lymphocytic leukemia (chronic lymphocytic leukemia, CLL) and lymphoma patients in vitro. The combination treatment of Venetoclax and the demethylated drug azacytidine or decitabine can achieve 70% complete remission and/or bone marrow remission (CR/CRi) of the primary senile AML, and has obviously lower toxic and side effects than conventional chemotherapy and good tolerance. In vivo experiments prove that the NL-101 single drug can reduce tumor load of AML mice and prolong survival time of the mice.
The combined use of Bcl-2 inhibitors and HDAC inhibitors for the synergistic treatment of AML patients has not been reported.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for synergistically and efficiently treating cancers, in particular AML.
To solve the above technical problem, the first aspect of the present invention provides a pharmaceutical composition comprising a Bcl-2 inhibitor and an HDAC inhibitor, wherein the molar ratio of Bcl-2 inhibitor to HDAC inhibitor is 1:1000-1:1.
Preferably, the Bcl-2 inhibitor is selected from the group consisting of ABT-737, navitocrax (ABT-263), HA14-1, obakla mesylate (GX 15-070) or Venetoclax (ABT-199).
More preferably, the Bcl-2 inhibitor is valneturab.
Preferably, the HDAC inhibitor is selected from vorinostat (SAHA), romidepsin (FK-228), belinostat (PXD 101), cilobutylamine (CS-055) or NL-101.
More preferably, the HDAC inhibitor is NL-101.
Preferably, the molar ratio of Bcl-2 inhibitor to HDAC inhibitor is 1:300-1:3.
Preferably, the molar ratio of Bcl-2 inhibitor to HDAC inhibitor is 1:1000, 1:300, 1:100, 1:30, 1:10, 1:3 or 1:1.
Preferably, the concentration of the Bcl-2 inhibitor is 1.0E-5. Mu.M, 3.0E-5. Mu.M, 1.0E-4. Mu.M, 3.0E-4. Mu.M, 0.001. Mu.M, 0.003. Mu.M, 0.01. Mu.M, 0.03. Mu.M, 0.1. Mu.M, 0.3. Mu.M or 1. Mu.M, and the concentration of the HDAC inhibitor is 0.03. Mu.M.
Preferably, the concentration of the Bcl-2 inhibitor is 1.0E-5. Mu.M, 3.0E-5. Mu.M, 1.0E-4. Mu.M, 3.0E-4. Mu.M, 0.001. Mu.M, 0.003. Mu.M, 0.01. Mu.M, 0.03. Mu.M, 0.1. Mu.M, 0.3. Mu.M or 1. Mu.M, and the concentration of the HDAC inhibitor is 0.1. Mu.M.
Preferably, the concentration of the Bcl-2 inhibitor is 1.0E-5. Mu.M, 3.0E-5. Mu.M, 1.0E-4. Mu.M, 3.0E-4. Mu.M, 0.001. Mu.M, 0.003. Mu.M, 0.01. Mu.M, 0.03. Mu.M, 0.1. Mu.M, 0.3. Mu.M or 1. Mu.M, and the concentration of the HDAC inhibitor is 0.3. Mu.M.
Preferably, the pharmaceutical composition is for inhibiting proliferation of an Acute Myelogenous Leukemia (AML) cell line; more preferably, the acute myelogenous leukemia cell line is MV4-11, molm-13 or THP-1 cell line or primary cell AML# 1 or AML# 12.
Preferably, the pharmaceutical combination index CI of the Bcl-2 inhibitor and the HDAC inhibitor in the pharmaceutical composition is less than 1. More preferably, the drug combination index CI is less than 0.5. Further preferred, the drug combination index CI is less than 0.2. Most preferably, the drug combination index CI is less than 0.1.
Preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, and the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:300-1:3.
More preferably, the Bcl-2 inhibitor vitamin E to HDAC inhibitor NL-101 molar ratio is 1:300, 1:100, 1:30, 1:10 or 1:3.
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:300-1:30, the concentration of the HDAC inhibitor is 0.3 mu M, and the pharmaceutical composition is used for inhibiting Acute Myelogenous Leukemia (AML) cell strain MV4-11.
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:100-1:10, the concentration of the HDAC inhibitor is 0.1 mu M, and the pharmaceutical composition is used for inhibiting Acute Myelogenous Leukemia (AML) cell strain MV4-11.
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:100-1:1, the concentration of the HDAC inhibitor is 0.03 mu M, and the pharmaceutical composition is used for inhibiting the THP-1 of Acute Myelogenous Leukemia (AML) cell line.
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-1:3, the concentration of the HDAC inhibitor is 0.1 mu M, and the pharmaceutical composition is used for inhibiting the THP-1 of Acute Myelogenous Leukemia (AML) cell line.
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-1:1, the concentration of the HDAC inhibitor is 0.3 mu M, and the pharmaceutical composition is used for inhibiting the THP-1 of Acute Myelogenous Leukemia (AML) cell line.
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-3:1, the concentration of the HDAC inhibitor is 0.03 mu M, and the pharmaceutical composition is used for inhibiting AML# 1 of primary cells of Acute Myelogenous Leukemia (AML).
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-10:1, the concentration of the HDAC inhibitor is 0.1 mu M, and the pharmaceutical composition is used for inhibiting AML# 1 of primary cells of Acute Myelogenous Leukemia (AML).
More preferably, the Bcl-2 inhibitor is vitamin A, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-10:1, the concentration of the HDAC inhibitor is 0.3 mu M, and the pharmaceutical composition is used for inhibiting AML# 1 of primary cells of Acute Myelogenous Leukemia (AML).
The second aspect of the invention provides a pharmaceutical preparation, which comprises the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutical formulation is selected from the group consisting of tablets, capsules, granules, suspensions, emulsions, aerosols, ointments or injections.
Preferably, the pharmaceutical formulation is administered by: oral administration, parenteral administration (e.g., inhalation, sublingual, rectal, transdermal, mucosal, nasal, ocular, etc.), injection administration (e.g., intramuscular injection, subcutaneous injection, intramedullary injection, intraperitoneal injection, intravenous injection, etc.), or other means of drug delivery.
In a third aspect, the present invention provides the use of a pharmaceutical composition or formulation as described above in the manufacture of a medicament for the treatment of cancer.
Preferably, the cancer is a hematological malignancy.
Preferably, the hematological malignancy is selected from Acute Myelogenous Leukemia (AML), acute Lymphoblastic Leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), chronic Lymphoblastic Leukemia (CLL), or Chronic Myelogenous Leukemia (CML).
More preferably, the hematological malignancy is selected from Acute Myelogenous Leukemia (AML).
Further preferred, the Acute Myelogenous Leukemia (AML) cell line is selected from MV4-11, molm-13 or THP-1 cell line or primary cell AML# 1 or AML# 12.
Most preferably, the Acute Myelogenous Leukemia (AML) cell line is selected from MV4-11 or THP-1 cell line or primary cell AML# 1.
Compared with the prior art, the invention has the beneficial effects that:
the present invention unexpectedly found that Bcl-2 inhibitors in combination with HDAC inhibitors produce a synergistic effect. Therefore, the combination of Bcl-2 inhibitors and HDAC inhibitors provides a safe and effective cancer treatment regimen for improving the clinical prognosis of AML patients, especially for elderly patients or patients with underlying diseases such as heart and lung, and with poor tolerance.
Drawings
FIG. 1 shows the inhibition of cell proliferation in AML cell lines MV4-11 by an ABT-199 single agent in combination with NL-101;
FIG. 2 shows the inhibition of cell proliferation in AML cell line Molm-13 by ABT-199 alone and in combination with NL-101;
FIG. 3 shows inhibition of cell proliferation in AML cell line THP-1 by ABT-199 alone and in combination with NL-101;
FIG. 4 shows inhibition of cell proliferation in AML primary cell AML # 1 by ABT-199 alone and in combination with NL-101;
FIG. 5 shows inhibition of cell proliferation in AML primary cells AML # 12 by an ABT-199 single agent in combination with NL-101;
FIG. 6 is a graph of the combined index of the synergistic interaction of ABT-199 and NL-101 with MV 4-11;
FIG. 7 is a graph of the combination index of ABT-199 acting in concert with NL-101 on Molm-13;
FIG. 8 is a graph of the association index of ABT-199 with NL-101 acting in concert with THP-1;
FIG. 9 is a graph of the combined index of the synergistic interaction of ABT-199 and NL-101 with AML primary cell AML# 1;
FIG. 10 is a graph showing the combined index of the synergistic interaction of ABT-199 and NL-101 with AML primary cell AML# 12.
Detailed Description
The following describes in detail the examples of the present invention, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
Test example 1 growth inhibitory Effect of Bcl-2 inhibitors in combination with HDAC inhibitors on AML cells
1. Test method
Cell proliferation assay (MTS colorimetric method)
Collecting AML cell lines (MV 4-11, molm-13, THP-1) in logarithmic growth phase and AML patient primary cells (AML# 1, AML#12), centrifuging, and re-suspending in fresh culture medium according to AML cell line 0.5-4×10 5 1X10 AML primary cells/mL 6 Density plating of/mL, 100. Mu.L of each well was inoculated into 96-well plates, three duplicate wells were plated per sample, corresponding concentrations of drug (NL-101 and ABT-199) were added, a blank was set, PBS was peripherally plated, and 100. Mu.L/well. 37 ℃ and 5% CO 2 After 48 hours of incubation in a concentration incubator, 10 mu L of LMTS working solution is added into each hole of a cell line, 20 mu L of MTS working solution is added into each hole of primary cells, the primary cells are continuously put into the incubator for incubation for 4 hours, the optical density (OD value) at 490nm wavelength is measured by an enzyme-labeling instrument, the OD value of each hole has positive correlation with the cell number, and the inhibition rate of cells with drug action and single drug IC are calculated 50 Cell proliferation was mapped using software GraphPad Prism and the combination index CI was calculated using CompuSyn software (CI value > 1 judged antagonistic; CI value > =1 judged additive; CI value < 1 judged synergistic).
2. Test results
To explore the synergistic effect of ABT-199 and NL-101 in AML cell lines and AML patient primary cells, drug sensitive experiments were performed on AML cell lines and AML primary cells, and were divided into ABT-199 single drug (concentration gradient 0. Mu.M, 1.0E-5. Mu.M, 3.0E-5. Mu.M, 1.0E-4. Mu.M, 3.0E-4. Mu.M, 0.001. Mu.M, 0.003. Mu.M, 0.01. Mu.M, 0.03. Mu.M, 0.3. Mu.M, 1. Mu.M), NL-101 single drug (concentration gradient 0.03. Mu.M, 0.1. Mu.M, 0.3. Mu.M) and combination treatment of both drugs.
The results of the experiments in FIGS. 1-3 show that the administration of ABT-199 alone and in combination with NL-101 on three AML cell lines (MV 4-11, molm-13, THP-1) inhibited cell proliferation to varying degrees and exhibited concentration dependence. In addition, the inhibition of cells by the combination of ABT-199 and NL-101 was significantly stronger than that of the ABT-199 alone. The sensitivity of different AML cell lines to ABT-199 and NL-101 was different.
The results of the experiments in FIGS. 4-5 show that the inhibition of cell proliferation by the combination of ABT-199 alone and with NL-101 on AML primary cells is greater for the combination of ABT-199 and NL-101 than for the combination of ABT-199 alone.
IC of ABT-199 acting on AML cell line and AML primary cell 50 The values are shown in table 1 below.
TABT-199 IC for different AML cell lines 50 Value of
| AML cell line | IC 50 (μM) |
| MV4-11 | 0.001228 |
| Molm-13 | 0.009397 |
| THP-1 | 0.3179 |
| |
0.0002428 |
| |
0.001207 |
The combination index of different concentration ratios of ABT-199 to NL-101 synergistically acts on the AML cell lines (MV 4-11, molm-13, THP-1) and AML primary cells (AML # 1, AML # 12) is shown in tables 2-6.
TABT-199 and NL-101 synergistic combination index for MV4-11
TABT-199 and NL-101 synergistic combination index for Molm-13
TABLE 4 association index of ABT-199 with NL-101 acting synergistically on THP-1
TABLE 5 combination index of ABT-199 and NL-101 acting synergistically on AML# 1
TABLE 6 combination index of ABT-199 and NL-101 acting synergistically on AML# 12
Drug combination effects plotted based on the data of tables 2-6 figures 6-10 show that ABT-199 in combination with NL-101 acts on MV4-11, molm13, THP-1 and the Combination Index (CI) values in primary cells AML # 1, AML # 12, respectively, are less than 1 in most molar ratio ranges, indicating that the combination of the two drugs has a synergistic effect in the cell lines and primary cells used in a broad molar ratio range.
Claims (1)
1. Use of a pharmaceutical composition comprising a Bcl-2 inhibitor and an HDAC inhibitor in a molar ratio of 1:300-1:30, wherein the Bcl-2 inhibitor is valnemulin, the HDAC inhibitor is NL-101, and wherein the cancer is acute myelogenous leukemia, for the preparation of a medicament for the treatment of cancer.
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| MX2011004344A (en) * | 2008-10-24 | 2011-11-18 | Gloucester Pharmaceuticals | Cancer therapy. |
| CN106957315B (en) * | 2016-01-08 | 2019-08-13 | 中国人民解放军第二军医大学 | N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of drug |
| CA3052594A1 (en) * | 2017-02-03 | 2018-08-09 | AI Therapeutics, Inc. | Methods for treating cancer using hsp90 inhibitors |
| US11597933B2 (en) * | 2017-11-29 | 2023-03-07 | The Trustees Of Columbia University In The City Of New York | Combination therapy of lymphoma |
| CN113813268A (en) * | 2020-06-18 | 2021-12-21 | 苏州亚盛药业有限公司 | Combination comprising a Bcl-2 inhibitor or a Bcl-2/Bcl-xL inhibitor and uses thereof |
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Non-Patent Citations (2)
| Title |
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| Novel SAHA‑bendamustine hybrid NL‑101 in combination with daunorubicin synergistically suppresses acute myeloid leukemia;Jingrui Jin等;《Oncol Rep.》;第44卷(第1期);273-282 * |
| Venetoclax-containing regimens in acute myeloid leukemia;Ibrahim Aldoss等;《Ther Adv Hematol》;12 * |
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