CN114588269A - Compositions of Bcl-2 inhibitors and HDAC inhibitors and uses thereof - Google Patents
Compositions of Bcl-2 inhibitors and HDAC inhibitors and uses thereof Download PDFInfo
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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 of the invention provides a safe and effective cancer treatment scheme for improving the clinical prognosis of AML patients, in particular for elderly patients or patients with combined 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 (AML) is a malignant clonal disease originated from hematopoietic stem cells, has strong heterogeneity, and is characterized in that the original cells in the bone marrow are clonally proliferated, have differentiation and maturation disorders, affect the growth of normal hematopoietic cells and invade multiple organs of the whole body. The total incidence 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 the prognosis of partial patients is improved by hematopoietic stem cell transplantation, novel targeted drugs and the like in recent years, chemotherapy is the most main treatment means for AML, the mortality rate caused by chemotherapy-related complications is high, tumor cell drug resistance is easy to occur, the treatment is ineffective, about 30 percent of patients are difficult to obtain Complete Remission (CR), the median survival time is only 3-6 months, and 50-80 percent of AML patients relapse after CR and have low recurrence rate after relapse; furthermore, patients with karyotype or high-risk molecular biological features have a poorer prognosis. Therefore, how to reduce the treatment-related toxic side effects and overcome tumor cell resistance is a hot and difficult point of current AML treatment.
In recent years, research on new drugs for AML at home and abroad is not in the way, for example, targeted drugs developed according to gene mutation, IDH1/2 inhibitors and FLT3 inhibitors are limited, so that the drugs can be only used for patients accompanied with corresponding gene mutation, and the curative effect of single-drug therapy is poor; epigenetics related drugs such as DNA methyltransferase inhibitors and histone deacetylase inhibitors have good curative effects on AML for the elderly, but are limited in applicable population and often need combined chemotherapy. Thus, the anthracycline and cytarabine based "3 + 7" regimen remains the first line treatment regimen for AML patients over the last 30 years. Ara-C belongs to pyrimidine antimetabolites, plays a role by inhibiting DNA polymerase and leading DNA damage by being doped into an extended DNA chain, is one of very effective medicaments for treating hematological malignancies, is a cornerstone in AML induction treatment and consolidation treatment at present, but an elderly patient cannot tolerate a large dose of Ara-C, lacks of the consolidation treatment of the large dose of Ara-C, and is one of causes of poor prognosis of the elderly AML patient. The cytotoxic mechanism of anthracyclines, represented by Daunorubicin (DNR), is DNA damage by insertion of DNA and inhibition of topoisomerase II, resulting in DNA Double Strand Breaks (DSBs) and induction of apoptosis. Although daunorubicin is most toxic in S phase, the drug is not cycle specific. However, the 3+7 scheme has obvious bone marrow suppression, more complications such as severe infection, bleeding and the like related to chemotherapy, and poor tolerance of old patients and patients with basic diseases such as heart, lung and the like. Reducing drug toxicity and reducing drug resistance while ensuring therapeutic efficacy is a challenge facing haematology researchers.
CPX-351 approved by the FDA of America is a daunorubicin and cytarabine liposome coated compound, so that the toxic and side effects are reduced, the curative effect is improved, and a new treatment idea is developed for scientific researchers. NL-101 (also called EDO-S101) is also designed based on the above principle, is a brand new small molecule compound formed by linking the DNA damage core group of bendamustine hydrochloride and the histone deacetylase inhibition core group of histone inhibitor vorinostat (also called SAHA) through covalent bonds, has the action mechanisms of the above two drugs, and can provide superior efficacy compared with a single drug. In vitro studies researchers have found that NL-101 is able to exert both histone deacetylase inhibitor (HDACI) effects (demonstrated by high acetylation of alpha-tubulin and histone) and DNA damage effects (shown by an increase in gamma-H2 AX) and is more potent than bendamustine single drug. In vivo experiments in mice prove that the curative effect of NL-101 is obviously better than that of SAHA and bendamustine single drugs. There is a need to search for drugs that combine with NL-101 to synergistically inhibit AML with good tolerance.
The occurrence, development and drug resistance of hematologic malignancies are highly dependent on the overexpression of the anti-apoptotic protein Bcl-2, Bcl-2 is an effective target for anti-tumor therapy, and high levels of Bcl-2 expression are closely associated with poor prognosis in AML patients. Venetosala (ABT-199) is a Bcl-2 small molecule inhibitor which is efficient, selective and bioavailable, and has strong affinity to Bcl-2. In vitro, venetocalax has strong killing activity against primary cells of Chronic Lymphocytic Leukemia (CLL) and lymphoma patients and cell lines of AML. The Venetocalax and the demethylation drug azacitidine or decitabine are combined to treat the primary treatment of the senile AML, 70 percent of complete remission and/or bone marrow remission (CR/CRi) can be obtained, the toxic and side effects are obviously lower than those of the conventional chemotherapy, and the tolerance is good. In vivo experiments prove that NL-101 single drug can reduce tumor load of AML mice and prolong survival time of the mice.
The combined application of Bcl-2 inhibitor and HDAC inhibitor to treat AML patient synergistically has not been reported.
Disclosure of Invention
The object of the present invention is to provide a pharmaceutical composition for synergistically and efficiently treating cancer, in particular AML.
In order to solve the technical problems, the invention provides a pharmaceutical composition comprising a Bcl-2 inhibitor and an HDAC inhibitor, wherein the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-1: 1.
Preferably, the Bcl-2 inhibitor is selected from ABT-737, Navitoclax (ABT-263), HA14-1, olbaccara mesylate (GX15-070) or Venetosela venetuma (ABT-199).
More preferably, the Bcl-2 inhibitor is venetolala.
Preferably, the HDAC inhibitor is selected from vorinostat (SAHA), romidepsin (FK-228), belinostat (PXD101), cidorelin (CS-055) or NL-101.
More preferably, the HDAC inhibitor is NL-101.
Preferably, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:300 to 1: 3.
Preferably, the molar ratio of the 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 used for inhibiting the proliferation of Acute Myeloid Leukemia (AML) cell line; more preferably, the acute myelogenous leukemia cell strain is MV4-11, Molm-13 or THP-1 cell strain or primary cell AML # 1 or AML # 12.
Preferably, the pharmaceutical composition has a Bcl-2 inhibitor and HDAC inhibitor combination index CI of less than 1. More preferably, the drug combination index CI is less than 0.5. Further preferably, 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 Venetulara, 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 molar ratio of the Bcl-2 inhibitor vernetorale to HDAC inhibitor NL-101 is 1:300, 1:100, 1:30, 1:10, or 1: 3.
More preferably, the Bcl-2 inhibitor is Venetura, 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 MV 4-11.
More preferably, the Bcl-2 inhibitor is Venetulla, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:100-1:10, the HDAC inhibitor is present at a concentration of 0.1 μ M, and the pharmaceutical composition is used for inhibiting Acute Myelogenous Leukemia (AML) cell strain MV 4-11.
More preferably, the Bcl-2 inhibitor is Venetura, 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 the Acute Myelogenous Leukemia (AML) cell strain.
More preferably, the Bcl-2 inhibitor is Venetulla, 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 the Acute Myelogenous Leukemia (AML) cell strain.
More preferably, the Bcl-2 inhibitor is Venetura, 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 the Acute Myelogenous Leukemia (AML) cell strain.
More preferably, the Bcl-2 inhibitor is vernital, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-3:1, the HDAC inhibitor is at a concentration of 0.03 μ M, and the pharmaceutical composition is for inhibiting Acute Myeloid Leukemia (AML) primary cell AML # 1.
More preferably, the Bcl-2 inhibitor is vernital, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-10:1, the HDAC inhibitor is at a concentration of 0.1 μ M, and the pharmaceutical composition is for inhibiting Acute Myeloid Leukemia (AML) primary cell AML # 1.
More preferably, the Bcl-2 inhibitor is vernital, the HDAC inhibitor is NL-101, the molar ratio of the Bcl-2 inhibitor to the HDAC inhibitor is 1:1000-10:1, the HDAC inhibitor is at a concentration of 0.3 μ M, and the pharmaceutical composition is for inhibiting Acute Myeloid Leukemia (AML) primary cell AML # 1.
The invention provides a pharmaceutical preparation, which comprises the pharmaceutical composition and pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutical preparation is selected from 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.), injectable administration (e.g., intramuscular injection, subcutaneous injection, intramedullary injection, intraperitoneal injection, intravenous injection, etc.), or other drug delivery means.
In a third aspect, the invention provides the use of the pharmaceutical composition or pharmaceutical preparation described above in the manufacture of a medicament for the treatment of cancer.
Preferably, the cancer is hematological malignancy.
Preferably, the hematological malignancy is selected from Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL) or Chronic Myeloid Leukemia (CML).
More preferably, the hematological malignancy is selected from Acute Myeloid Leukemia (AML).
Further preferably, the Acute Myeloid 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 Myeloid 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 finds that a Bcl-2 inhibitor in combination with an HDAC inhibitor produces a synergistic effect. Therefore, the drug combination of the Bcl-2 inhibitor and the HDAC inhibitor provides a safe and effective cancer treatment scheme for improving the clinical prognosis of AML patients, particularly for old patients or patients with basic diseases such as heart and lung and poor tolerance.
Drawings
FIG. 1 shows the cell proliferation inhibition of ABT-199 in AML cell line MV4-11 as a single agent and in combination with NL-101;
FIG. 2 shows the cell proliferation inhibition of the ABT-199 single drug and combination NL-101 in AML cell line Molm-13;
FIG. 3 shows the cell proliferation inhibition of ABT-199 in AML cell line THP-1 as a single agent and in combination with NL-101;
FIG. 4 shows the cell proliferation inhibition of ABT-199 in primary AML cells AML # 1, alone and in combination with NL-101;
FIG. 5 shows the cell proliferation inhibition of ABT-199 in AML primary cells AML # 12 as a single agent and in combination with NL-101;
FIG. 6 is a graph of the joint index of ABT-199 in synergy with NL-101 for MV 4-11;
FIG. 7 is a graph of the joint index of the synergy of ABT-199 and NL-101 on Molm-13;
FIG. 8 is a graph of the joint index of the synergy of ABT-199 with NL-101 on THP-1;
FIG. 9 is a graph of the combined index of ABT-199 and NL-101 acting synergistically on AML primary cell AML # 1;
FIG. 10 is a graph of the combined index of ABT-199 and NL-101 acting synergistically on AML primary cell AML # 12.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Experimental example 1 growth inhibitory Effect of Bcl-2 inhibitor in combination with HDAC inhibitor on AML cells
1. Test method
Cell proliferation assay (MTS colorimetric method)
Collecting AML cell strains (MV4-11, Molm-13, THP-1) in logarithmic growth phase and primary cells (AML # 1, AML #12) of AML patients, centrifuging, suspending in fresh culture medium, and culturing according to AML cell line 0.5-4 × 105AML primary cells 1X 10/mL6Density of/mL plated, 100 μ L per well in 96-well plates, triplicate wells per sample, addition of corresponding concentrations of drug (NL-101 and ABT-199), setting blank control, peripheral plating with PBS, 100 μ L per well. 37 ℃ and 5% CO2After 48 hours of incubation in an incubator with concentration, 10 mu L of LMTS working solution is added into each hole of the cell line, 20 mu L of MTS working solution is added into each hole of the primary cells, the primary cells are continuously placed into the incubator for incubation for 4 hours, the optical density (OD value) at the 490nm wavelength is measured by using an enzyme-labeling instrument, the OD value of each hole is in positive correlation with the number of the cells, and the inhibition rate of the drug-acting cells and the single-drug IC are calculated50The cell proliferation was mapped using GraphPad Prism software and the combination index CI (CI > 1 for antagonism; CI > -1 for additivity; CI < 1 for synergy) was calculated using CompuSyn software.
2. Test results
To find that ABT-199 and NL-101 showed synergistic effect in AML cell lines and AML patient primary cells, drug sensitivity experiments were conducted on AML cell lines and AML primary cells, and they were classified into ABT-199 single drug (concentration gradient of 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, 0.1. mu.M, 0.3. mu.M, 1. mu.M), NL-101 single drug (concentration gradient of 0.03. mu.M, 0.1. mu.M, 0.3. mu.M), and two drugs in combination.
The results of the experiments in FIGS. 1-3 show that ABT-199, alone and in combination with NL-101, act on three AML cell lines (MV4-11, Molm-13, THP-1) with varying degrees of inhibition of cell proliferation and concentration dependence. In addition, the combined group of ABT-199 and NL-101 has obviously stronger cell inhibition effect than that of the single group of ABT-199. Different AML cell lines have different sensitivities to ABT-199 and NL-101.
The results of the experiments in FIGS. 4-5 show that ABT-199 acting on AML primary cells in combination with NL-101 inhibited cell proliferation, and that the combination of ABT-199 and NL-101 had a stronger inhibitory effect on cell growth than the ABT-199 single drug group.
ABT-199 IC acting on AML cell line and AML primary cell50The values are shown in table 1 below.
TABLE 1 IC of ABT-199 against different AML cell lines50Value of
| AML cell line | IC50(μM) |
| MV4-11 | 0.001228 |
| Molm-13 | 0.009397 |
| THP-1 | 0.3179 |
| |
0.0002428 |
| |
0.001207 |
The combination index of the synergistic effect of ABT-199 and NL-101 at different concentrations on AML cell lines (MV4-11, Molm-13, THP-1) and AML primary cells (AML # 1, AML #12) is shown in tables 2-6.
TABLE 2 combination index of synergy of ABT-199 with NL-101 on MV4-11
TABLE 3 combination index of synergy of ABT-199 with NL-101 on Molm-13
TABLE 4 combination index of synergy of ABT-199 with NL-101 on THP-1
TABLE 5 combination index of ABT-199 and NL-101 synergy on AML # 1
TABLE 6 combination index of synergy of ABT-199 and NL-101 on AML # 12
Drug combination effects plotted based on the data in tables 2-6 figures 6-10 show that the Combination Index (CI) values for ABT-199 in combination with NL-101 in MV4-11, Molm13, THP-1 and primary cells AML # 1, AML # 12, respectively, were less than 1 over most of the molar ratio range, indicating that the two drugs used in combination in the cell lines and primary cells described above have a synergistic effect over a wide molar ratio range.
Claims (10)
1. A pharmaceutical composition comprising a Bcl-2 inhibitor and an HDAC inhibitor in a molar ratio of 1:1000 to 1:1 of the Bcl-2 inhibitor to the HDAC inhibitor.
2. The pharmaceutical composition of claim 1, wherein the Bcl-2 inhibitor is selected from ABT-737, Navitoclax, HA14-1, olbaccara mesylate, or vernetorale.
3. The pharmaceutical composition of claim 2, wherein the Bcl-2 inhibitor is venetola.
4. The pharmaceutical composition of claim 1, wherein the HDAC inhibitor is selected from vorinostat, romidepsin, belinostat, cidentamine or NL-101.
5. The pharmaceutical composition of claim 4, wherein the HDAC inhibitor is NL-101.
6. The pharmaceutical composition of claim 1, wherein the molar ratio of the Bcl-2 inhibitor to HDAC inhibitor is 1:300 to 1: 3.
7. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-6 and a pharmaceutically acceptable excipient.
8. Use of a pharmaceutical composition according to any one of claims 1 to 6 or a pharmaceutical formulation according to claim 7 for the manufacture of a medicament for the treatment of cancer.
9. The use according to claim 8, wherein the cancer is hematological malignancy.
10. Use according to claim 9, characterized in that the hematological malignancy is selected from Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL) or Chronic Myelogenous Leukemia (CML).
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| US20110269699A1 (en) * | 2008-10-24 | 2011-11-03 | Mitchell Keegan | Cancer therapy |
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| US20180221376A1 (en) * | 2017-02-03 | 2018-08-09 | Lam Therapeutics, Inc. | Methods for treating cancer using HSP90 inhibitors |
| US20200263185A1 (en) * | 2017-11-29 | 2020-08-20 | 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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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110269699A1 (en) * | 2008-10-24 | 2011-11-03 | Mitchell Keegan | Cancer therapy |
| CN106957315A (en) * | 2016-01-08 | 2017-07-18 | 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 medicine |
| US20180221376A1 (en) * | 2017-02-03 | 2018-08-09 | Lam Therapeutics, Inc. | Methods for treating cancer using HSP90 inhibitors |
| US20200263185A1 (en) * | 2017-11-29 | 2020-08-20 | 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 |
Non-Patent Citations (2)
| Title |
|---|
| IBRAHIM ALDOSS等: "Venetoclax-containing regimens in acute myeloid leukemia", 《THER ADV HEMATOL》, pages 12 * |
| JINGRUI JIN等: "Novel SAHA‑bendamustine hybrid NL‑101 in combination with daunorubicin synergistically suppresses acute myeloid leukemia", 《ONCOL REP.》, vol. 44, no. 1, pages 273 - 282 * |
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