WO2023006954A1 - Asenapine for use in cancer - Google Patents
Asenapine for use in cancer Download PDFInfo
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- WO2023006954A1 WO2023006954A1 PCT/EP2022/071374 EP2022071374W WO2023006954A1 WO 2023006954 A1 WO2023006954 A1 WO 2023006954A1 EP 2022071374 W EP2022071374 W EP 2022071374W WO 2023006954 A1 WO2023006954 A1 WO 2023006954A1
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Definitions
- the present invention relates to the therapeutical indication of asenapine in cancer. It also relates to drug combinations of asenapine and other anticancer agents, as well as to pharmaceutical compositions and kits containing them, and to the use of the latter in medicine, in particular as anticancer agents.
- Cancer is the second leading cause of death worldwide, accounting for an estimated almost 10.0 million deaths in 2020, and the number of cancer patients has increased year by year.
- the most common types of cancer in men are lung, prostate, colorectal, stomach and liver cancer, while among women breast, colorectal, lung, cervical and thyroid cancer are the most common.
- Cancer is currently treated by a number of methods including surgery, radiotherapy, chemotherapy and molecular-targeted therapy.
- Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women. Lung cancer is by far the leading cause of cancer death among both men and women, making up almost 25% of all cancer deaths. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined.
- Brain and central nervous system (CNS) cancers represent around 1.7% of the total cancer cases and are two of the primary cancers that affect children and young adults.
- brain cancers including for example neuroblastoma are the most common solid tumor and the leading cause of death from cancer among children.
- gliomas which represent 45 - 55% of all primary cerebral tumors, are the most common of the CNS tumors.
- Glioblastoma is an aggressive glioma that is notoriously difficult to treat due to its diffuse infiltration into surrounding tissue.
- Conventional treatment of brain tumors include surgery, radiation therapy and chemotherapy. Despite improvements in surgery techniques and therapeutic protocols, patients with this type of cancers usually often show poor prognosis.
- chemotherapeutic efficacy in brain tumors is limited by toxic effects on healthy cells and also by the ability of the drugs to cross the blood-brain barrier (BBB).
- BBB blood-brain barrier
- Cancer is a heterogeneous group of diseases that results not just from aberrant cellular proliferation but also from lack of well-regulated cell death. Resistance to apoptosis is one important evasion mechanism by which tumor cells may present chemoresistance and thus contribute to cancer progression. Consequently, molecules involved in regulation of apoptosis are considered potential targets for cancer therapy.
- Survivin is a small protein that belongs to the inhibitor of apoptosis (IAP) protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in many human neoplasms. Overexpression of survivin has been strongly associated with inhibition of the intrinsic and extrinsic cell death pathway. Survivin also seems to play an important role in cell division.
- IAP inhibitor of apoptosis
- Antipsychotic drugs are commonly classified into two different groups: typical antipsychotics, also known as first-generation antipsychotics (FGAs), and atypical antipsychotics, also known as second-generation antipsychotics (SGAs). While FGAs have been classified according to their chemical structure, SGAs are grouped by their pharmacological properties. SGAs’ mechanisms of action and side-effects differ significantly from drug to drug. Asenapine is the generic name of the chemical compound 5-chloro-2-methyl-2,3,3a,12b- tetrahydrodibenzo[2,3:6,7]oxepino[4,5-c]pyrrole.
- Asenapine is a trans-racemate composed by a mixture of the following enantiomers: Asenapine is an atypical antipsychotic sold in the form of its maleate salt under the brand name Saphris, among others. It is used to treat schizophrenia and acute mania associated with bipolar disorder. Asenapine, as well as processes for its preparation, were described for the first time in US4145434.
- the Chinese patent application WO2016062285 discloses anticancer compositions containing drugs used for treating nervous system diseases.
- Asenapine is mentioned as an example of this class of drugs.
- Table 3 reports data on the inhibition of asenapine among a very long list of other active agents against the following cancer cell lines: H1650 (lung adenocarcinoma), A549 (lung adenocarcinoma), AGS (gastric adenocarcinoma), MKN-45 (gastric adenocarcinoma), HepG2 (Hepatocellular carcinoma), HCT116 (colorectal carcinoma), LoVo (colorectal adenocarcinoma), A375 (amelanotic melanoma), HeLa (cervix adenocarcinoma), PC3 (prostate adenocarcinoma), TSGH-8301 (urinary bladder carcinoma), MCF7 (mammary Gland adenocarcinoma), and HL-60 (acute promy
- Zhang W. et al. (Sci Rep 2018 Oct 25;8(1): 15753) discloses that FGAs have been explored as agents against untreatable brain metastases because of their ability to cross the blood-brain barrier (BBB), but that they have shown limited clinical application because FGAs are associated with a spontaneous death risk, especially in elderly patients.
- Zhang et al. investigated antitumor activities of eight SGAs, including asenapine, toward a breast cancer (TNBC) cell line.
- TNBC breast cancer
- EP3708161 discloses the use of 6 compounds for preventing or treating a disease or symptom caused by mitochondrial dysfunction.
- These compounds include an anti-Parkinson agent (compound 1-1), 3 FGAs (compounds I-4, I-5, and I-6), and 2 SGAs including olanzapine (compound I-3) and asenapine (compound I-2).
- Cancer is cited among the list of diseases or symptoms caused by mitochondrial dysfunction.
- asenapine may be effectively used in the treatment of cancer.
- asenapine did not show any inhibitory effects on cancer cell lines (WO2016062285) or discarded asenapine for further testing against cancer based on the available results (Zhang W. et al.)
- asenapine is not only able to show moderate anticancer activity against several cancer cell lines in vitro, but also antitumoral effects in vivo.
- asenapine reduced the cell viability in lung adenocarcinoma (A549), and colon adenocarcinoma (SW620) cancer cell lines with statistical significance, while not being cytotoxic to healthy cells (FIG. 1).
- Asenapine also showed in vitro anticancer effects against pediatric neuroblastoma (LAN-1), pediatric sarcoma (RD), and glioblastoma (U87) (FIG. 2) in the same range of efficacy as other approved chemotherapeutics such as cisplatin.
- asenapine also showed antitumoral activity in vivo in a subcutaneous tumor mice model of lung carcinoma (FIG. 7, 8).
- the administration of asenapine at doses of 10, 15 and 20 mg/kg did not show any significant toxicity, it did not affect mice growth (FIG. 5) nor organs weight (FIG. 6).
- asenapine may be advantageously used in combination with classical chemotherapeutic agents or other anticancer agents and provide an improved treatment thanks to a synergistic anticancer effect attained by the drug combination.
- chemotherapeutic agents such as cisplatin, carboplatin, and gemcitabine acted synergistically against cancer in vitro and in vivo (FIG. 9, FIG. 10 and FIG. 11).
- the fact that the drug combinations of the invention show synergistic effects may allow the use of lower dosages of one or more of the therapeutic agents of the combination, and/or less frequent administration of the drugs.
- the use of these drug combinations may lead to a reduction of potential adverse side-effects, which is highly desirable for improving the quality of life of the patients, but without reducing the efficacy of the therapy.
- asenapine s role in the treatment of cancer could be related to its ability to inhibit survivin.
- the main established functions of survivin are the regulation of cell mitosis and the inhibition of apoptosis.
- the present inventors found that asenapine shows high affinity to the ligand survivin (FIG. 3) and, in particular, is able to specifically inhibit survivin protein levels (FIG. 4). This mechanism was unknown so far to the best knowledge of the inventors.
- asenapine would be able to i) induce apoptosis in tumor cells; ii) inhibit cell cycle; and iii) sensitize tumor cells to standard chemotherapeutic agents or other anticancer agents, without being toxic to healthy cells.
- a first aspect of the invention relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its salts for use in the treatment and/or prevention of cancer.
- a second aspect of the invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
- a third aspect of the invention relates to a drug combination comprising: a) compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its salts, as defined herein, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
- a fourth aspect of the invention relates to a single pharmaceutical composition which comprises: a) a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein; b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein; and one or more pharmaceutically acceptable excipients or carriers.
- a fifth aspect of the invention relates to a kit of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions.
- a sixth aspect of the invention relates to the drug combination, the single pharmaceutical composition, or the package or kit of parts as defined herein, for use in the treatment and/or prevention of cancer.
- a seventh aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts, for use in combination therapy in the treatment and/or prevention of cancer, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein, is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein.
- An eighth aspect of the invention relates to one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents for use in combination therapy in the treatment and/or prevention of cancer, wherein the one or more anticancer agents are to be administered simultaneously, concurrently, separately or sequentially with a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein.
- a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein.
- FIG. 1 shows the percentage of MTT cell viability (%V) after 24 h of treatment with asenapine at 5 and 20 mM in normal human lung fibroblast (HFL-1), lung adenocarcinoma (A549) and colon adenocarcinoma (SW620) with respect to control (Ctl). Bars represent the mean ⁇ SD. Statistically significant results are indicated as *, p-value ⁇ 0.05; **, p- value ⁇ 0.01 and ***, p-value ⁇ 0.001.
- FIG. 2 shows the percentage of MTT cell viability (%V) after 24 h of treatment with AM at concentrations ranging from 0.8 to 100 mM in lung adenocarcinoma (A549), colon adenocarcinoma (SW620), pediatric neuroblastoma (LAN-1), pediatric sarcoma (RD), and glioblastoma (U87) cancer cell lines. Results are shown as mean ⁇ SD.
- FIG. 3 shows binding to survivin of AM and Abbot23b.
- A Association and dissociation experimental curves for binding (concentrations of Abbot23b and AM ranging from 0.012 to 40 pM) to immobilized survivin (Calmodulin tag) analyzed by SPR.
- B Affinity curves data.
- FIG. 4 shows the decrease of survivin levels in cells in vitro treated with AM with respect to control (Ctl).
- IC50 value of AM the expression of survivin and XIAP was analyzed by Western blot analysis in A549 cell line. Protein levels were normalized with their respective loading controls.
- F.C. fold change). Bars represent the mean ⁇ SD. Statistically significant results are indicated as *, p-value ⁇ 0.05; **, p-value ⁇ 0.01 and ***, p-value ⁇ 0.001.
- FIG. 5 shows the mice growth (%W) during the toxicity study as difference of weight in percentage respect to initial weight, after treating mice with 10, 15 and 20 mg/kg of AM or vehicle (V) for 5 days per week. Results are shown as mean ⁇ SEM. t (d): time in days.
- FIG. 6 shows the organs weight during the toxicity as percentage of mice weight after treating mice with 10, 15 and 20 mg/kg of AM or vehicle (V) for 5 days per week. Results are shown as mean ⁇ SD.
- 0 organs
- T.W. total weight
- K kidneys
- L liver
- S spleen
- B brain.
- FIG. 7 shows the mice growth (%W) during the efficacy study as difference of weight in percentage respect to initial weight after treating C57BL/6 mice, inoculated with mouse Lewis lung carcinoma cell line (LLC1), with 10 mg/kg of AM or vehicle (V) for 5 days per week. Results are shown as mean ⁇ SEM. t (d): time in days.
- FIG. 8 shows the tumor volume (T.V.) during the efficacy assay after treating C57BL/6 mice, inoculated with mouse Lewis lung carcinoma cell line (LLC1), with 10 mg/kg of AM or vehicle (V). Results are shown as mean ⁇ SEM. t (d): time in days.
- FIG. 9 shows the MTT assay performed after 24 h of treatment with AM or AM plus a chemotherapeutic (cisplatin (CisPt), or carboplatin (CbPt)) in lung adenocarcinoma (A549).
- A IC50 value of the chemotherapeutic alone versus IC50 of the combination.
- B Percentage of cell viability (V) alone (CisPt 0.1 mg/ml_, CbPt 0.25 mg/ml_) or in combination treatment.
- C fractional inhibition (FA) of the chemotherapeutic and the combined treatment.
- FIG. 10 shows the MTT assay performed after 24 h of treatment with AM or AM plus a chemotherapeutic (gemcitabine (Gem)) in lung adenocarcinoma (A549).
- A IC50 value of the chemotherapeutic alone versus IC50 of the combination.
- B Percentage of cell viability (V) alone (4 mg/ml_) or in combination treatment.
- C fractional inhibition (FA) of the chemotherapeutic and the combined treatment.
- D combination index (Cl) of the treatment at different concentrations of chemotherapeutics.
- FIG. 11 shows the therapeutic effect of AM and AM in combination with cisplatin (CisPt).
- A) shows mice growth (%W) during the combination efficacy study as difference of weight (in percentage) respect to initial weight, after treating C57BL/6 mice subcutaneously inoculated with mouse Lewis lung carcinoma cell line (LLC1), with AM (5 mg/kg, 5 days per week), cisplatin (3 mg/kg on days 0, 3 and 6), AM plus CisPt in combination or vehicle (V).
- B) shows the tumor volume (T.V.) during the combination efficacy assay after treating C57BL/6 mice subcutaneously inoculated with LLC1 cells, with AM, CisPt, CisPt+AM or vehicle.
- T.W. tumor weight at the end of the combination efficacy assay after treating C57BL/6 mice subcutaneously inoculated with LLC1 cells, with AM, CisPt, CisPt+AM or vehicle. Results are shown as mean ⁇ SEM.
- Statistical analysis was subjected to One-way ANOVA test, with Tukey test for multiple comparisons.
- the invention relates to a compound of formula (I) or a stereoisomer and/or a salt thereof, for use in the treatment and/or prevention of cancer.
- stereoisomer refers to all isomers of individual compounds that differ only in the orientation of their atoms in space.
- stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric isomers (cis/trans or syn/anti), and isomers that are not mirror images of one another (diastereoisomers).
- the present invention relates to each of these stereoisomers and also to mixtures thereof.
- Diastereoisomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization.
- Optical isomers can be individually obtained using enantiospecific synthesis or can be resolved by conventional techniques of optical resolution to give optically pure isomers.
- salt of the compound of formula (I) there is no limitation on the type of salt of the compound of formula (I) that can be used, provided that these are pharmaceutically acceptable when they are used for therapeutic purposes.
- pharmaceutically acceptable salts embraces non-toxic salts commonly used.
- the preparation of pharmaceutically acceptable salts of the compound of formula (I) can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic moiety, by reacting it with a stoichiometric amount of an appropriate pharmaceutically acceptable inorganic or organic acid, in water or in an organic solvent or in a mixture of them.
- the compound of formula (I) and its salts may differ in some physical properties, but they are equivalent for the purposes of the present invention.
- Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula (I) which can be used for the purposes of the present invention include acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, lactate, maleate, oxalate, fumarate.
- the compound of formula (I) is in the form of its maleate salt.
- the compound of formula (I) or its stereoisomers and/or salts may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates). All these forms are within the scope of the present invention. Methods of solvation are generally known within the art. In general, the solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention. In all embodiments of the invention referring to the compound of formula (I), its pharmaceutically acceptable salts thereof as well as the stereoisomers or mixtures of stereoisomers, either of any of the compound of formula (I), or of any of its pharmaceutically acceptable salts, are always contemplated even if they are not specifically mentioned.
- the compound of formula (I) is selected from the group consisting of a compound of formula (la), a compound of (lb), a racemic mixture of a compound of formula (la) and a compound of (lb), and a pharmaceutically acceptable salt of any of them
- the compound of formula (I) is a racemic mixture of a compound of formula (la) and a compound of (lb), or a pharmaceutically acceptable salt thereof.
- the compound of formula (I) is asenapine, more particularly asenapine maleate.
- the invention also relates to a drug combination comprising a) compound of formula (I) or a stereoisomer and/or a salt thereof as defined herein, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
- the drug combination comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) one or more chemotherapy agents.
- one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents refers to exactly one but also to more than one, such as two, three, and so on.
- the term “one or more” does not define the actual number of one type of anticancer agent but refers to the number of distinct molecules of the recited class.
- the drug combination comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) one anticancer agent selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents, more particularly one chemotherapy agent.
- the drug combination comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) two anticancer agents, which may belong to the same or to a different class, selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
- chemotherapy or chemotherapeutic agent refers to cytotoxic, cytostatic, and antineoplastic agents that preferentially kill, inhibit the growth of, or inhibit the metastasis of neoplastic cells or disrupt the cell cycle of rapidly proliferating cells.
- antimetabolites As chemotherapy agents, the following may be used: antimetabolites, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antitumor antibiotics, protein kinase inhibitors, enzymes, proteasome inhibitors, PARP inhibitors, histone deacetylase inhibitors.
- antimetabolites in the context of the invention refers to compounds that are functionally distinct but structurally similar to, biological components involved in growth regulating biochemical reactions, called metabolites. Antimetabolites block cell division and inhibit growth related pathways by replacing required biological components (metabolites) and preventing their functioning.
- Non-limiting examples of antimetabolites include antifolates, such as methotrexate, and pemetrexed; pyrimidine antagonists such as cytarabine, 5-fluorouracil (5-FU), capecitabine, and gemcitabine; purine antagonists, such as 6-mercaptopurine (6-MP), azathioprine, fludarabine, and cladribine; or ribonucleotide reductase inhibitors, such as hydroxyurea.
- pyrimidine antagonists such as cytarabine, 5-fluorouracil (5-FU), capecitabine, and gemcitabine
- purine antagonists such as 6-mercaptopurine (6-MP), azathioprine, fludarabine, and cladribine
- ribonucleotide reductase inhibitors such as hydroxyurea.
- alkylating agents refers to any antineoplastic compound that irreversibly binds to a variety of susceptible biomolecules such
- platinum compounds refers to alkylating agents which are coordination complexes of platinum that bind DNA, resulting in ineffective DNA damage repair and, ultimately, the death of the cancer cell.
- alkylating agents include oxazaphosphorines, such as cyclophosphamide and ifosfamide; nitrogen mustards, such as chlorambucil and melphalan; imidazotetrazines, such as temozolomide; nitrosoureas, such as carmustine, lomustine, and streptozocin; alkyl sulfonates, such as busulfan; hydrazines, such as procarbazine; or platinum-based agents, such as cisplatin, carboplatin, and oxaliplatin.
- oxazaphosphorines such as cyclophosphamide and ifosfamide
- nitrogen mustards such as chlorambucil and melphalan
- imidazotetrazines such as temozolomide
- nitrosoureas such as carmustine, lomustine, and streptozocin
- alkyl sulfonates such as busulfan
- topoisomerase inhibitors refer to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of topoisomerase enzymes, including topoisomerase I and topoisomerase II.
- topoisomerase inhibitors include topoisomerase I inhibitors, such as irinotecan, and topotecan; and topoisomerase II inhibitors, such as etoposide, and teniposide.
- mitotic inhibitor refers to compounds which inhibit mitosis or cell division by disrupting microtubules.
- Non-limiting examples of mitotic inhibitors include vinca alkaloids, such as vincristine, vinblastine, and vinorelbine; taxanes, such as docetaxel, and paclitaxel; or nontaxane microtubule inhibitors, such as eribulin, ixabepilone, and epothilone.
- antitumor antibiotics refer to antibiotics having antitumor activity, and includes substances that inhibit the growth or other functions of cells in microorganisms or other organisms.
- Non-limiting examples of antitumor antibiotics include bleomycin, actinomycin D, anthracyclines, such as doxorubicin, daunorubicin, and idarubicin; or mitomycin.
- kinase inhibitors refers to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of one or more protein kinases.
- protein kinase inhibitors include BCR-ABL tyrosine kinase inhibitors and c- KIT tyrosine kinase inhibitors, such as imatinib, dasatinib, and nilotinib; EGFR tyrosine kinase inhibitors, such as erlotinib, gefitinib, afatinib, and osimertinib; ALK tyrosine kinase inhibitors, such as alectinib, and crizotinib; V600E mutated-BRAF oncogene inhibitors, such as dabrafenib, vemurafenib, and encorafenib; MEK inhibitors, such as trametinib;
- proteasome inhibitors refers to compounds that totally or partially reduce, inhibit, interfere with or modulate at least one enzymatic activity of the proteasome. These compounds prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro- apoptotic pathways.
- proteasome inhibitors include bortezomib, carfilzomib, and ixazomib.
- PARP inhibitor refers to an inhibitor or antagonist of poly(ADP- ribose) polymerase activity.
- PARP inhibitors include compounds which specifically inhibit a particular PARP protein or proteins, such as PARP1 and/or PARP2.
- Non-limiting examples of PARP inhibitors include olaparib.
- histone deacetylase inhibitor refers to a compound that selectively targets, decreases, or inhibits at least one activity of a histone deacetylase.
- Histone deacetylase inhibitors include vorinostat and romidepsin.
- Non-limiting examples of enzymes include L-asparaginase.
- hormone therapy agents in the context of the invention refers to proteins or substances that help to control cancers depend on hormones to grow. Treating cancer with hormones is called hormone therapy, hormonal therapy, or endocrine therapy. Hormone therapy is mostly used to treat certain kinds of breast cancer and prostate cancer that depend on sex hormones to grow.
- Non-limiting examples of hormone therapy include aromatase inhibitors (Als), such as anastrozole, exemestane, and letrozole; selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene; estrogen receptor antagonists, such as fulvestrant and toremifene; anti-androgens, such as apalutamide, enzalutamide, darolutamide, bicalutamide, flutamide, and nilutamide; CYP17 inhibitors, such as abiraterone and ketoconazole; luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, such as goserelin, leuprolide, triptorelin, and degarelix; progestins, such as medroxyprogesterone acetate or megestrol acetate; or adrenolytics, such as mitotane.
- Aromatase inhibitors such as anastrozo
- immunotherapy agents refers to those agents which use the own immune system to fight cancer. Immunotherapy can boost or change how the immune system works so it can find and attack cancer cells.
- immunotherapy agents include immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab; interferons, interleukins, oncolytic viruses, chimeric antigen receptor T cell (CAR-T) products or cytokines.
- the chemotherapy agents are selected from the group consisting of antimetabolites, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antitumor antibiotics, protein kinase inhibitors, enzymes, proteasome inhibitors, PARP inhibitors, histone deacetylase inhibitors.
- the drug combination of the invention comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, in particular asenapine or a salt thereof, and b) one or more anticancer agents selected from the group consisting of methotrexate, pemetrexed, cytarabine, 5-fluorouracil (5-FU), capecitabine, gemcitabine, 6-mercaptopurine (6-MP), azathioprine, fludarabine, cladribine, hydroxyurea, cyclophosphamide, ifosfamide, chlorambucil, melphalan, temozolomide, carmustine, lomustine, streptozocin, busulfan, procarbazine, cisplatin, carboplatin, oxaliplatin, irinotecan, topotecan, etoposide, ten, methotrexate, pemetrexed, cytarabine, 5-fluorouracil
- the drug combination is selected from the group consisting of: i) a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) cisplatin, ii) a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) carboplatin, iii) a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) gemcitabine.
- the drug combinations comprising a) a compound of formula (I), or a stereoisomer and/or a salt thereof, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents act synergistically against cancer as illustrated in the examples.
- synergy or synergistic refers to the fact that the effect observed by the combination is greater than the sum of the effects (additive effect) obtained independently with each one of the components of the drug combination.
- the synergy can be determined e.g. by Compusyn software analysis of cell viability assays results.
- the present invention also relates to pharmaceutical compositions comprising the compounds of formula (I), or stereoisomers and/or a salt thereof as previously defined, as well as to pharmaceutical compositions and kits of parts comprising the drug combinations defined herein.
- the invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a stereoisomer and/or a salt thereof, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
- the compound of formula (I) or a salt and/or a stereoisomer thereof is the only active ingredient of the composition.
- the invention also relates to a single pharmaceutical composition which comprises: a) a therapeutically effective amount of a compound of formula (I), or a salt and/or a stereoisomer thereof; b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents; and one or more pharmaceutically acceptable excipients or carriers.
- single pharmaceutical composition refers to a dosage form that contains both a) and b) in the same composition.
- the present invention also relates to a kit of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound of formula (I), or a salt and/or a stereoisomer thereof, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions.
- the term “kit-of-parts or package” refers to a combined preparation, wherein the active ingredients a) and b) are physically separated and form part of different compositions although these compositions are packaged or marked for use together.
- “for use together or in combination” does not limit the order in which the therapeutic agents are administered.
- the compound of formula (I) or a salt and/or a stereoisomer thereof may be administered prior to, concomitantly with, or subsequent to the administration of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
- therapeutically effective amount refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
- the specific dose of the compound to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration.
- pharmaceutically acceptable excipients or carriers refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
- Suitable pharmaceutical compositions to be used in the present invention are well-known in the art.
- the election of the pharmaceutical formulation will be determined by the skilled person depending upon the nature of the active compounds present in the composition, and its route of administration. Any route of administration may be used, for example oral, parenteral and topical administration.
- the pharmaceutical composition may be formulated for oral administration and may contain one or more physiologically compatible carriers or excipients, in solid or liquid form.
- formulations suitable for oral administration may include liquid solutions, suspensions, capsules, sachets or tablets, emulsions or dry powdered forms suitable for reconstitution with water.
- the pharmaceutical composition may also be formulated for parenteral administration in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
- conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions.
- These pharmaceutical compositions may be injected intramuscularly, intraperitoneally, or intravenously.
- the pharmaceutical composition may also be formulated for topical administration.
- Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients. These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. Uses
- the compounds of formula (I) and stereoisomers and/or salts thereof, as well as the drug combinations disclosed herein, are useful in the treatment and/prevention of cancer.
- treat, treatment or treating refer to having a therapeutic effect, in particular to ameliorating symptoms associated with a disease or disorder, including delaying the onset of the disease or disorder symptoms, and/or lessening the severity or frequency of symptoms of the disease or disorder. Treating includes inhibition of tumor growth, maintenance of inhibited tumor growth, induction of remission, and metastasis of a tumor.
- prevent, prevention or preventing refers to decreasing the probability that an organism contracts or develops an abnormal condition.
- cancer and tumor as used herein interchangeably to refer to the pathological condition in mammals, including humans, that is typically characterized by unregulated cell growth. While these terms may include both benign or malignant growths, it is of particular interest of this invention the treatment and/or prevention of malignant tumors and cancers which are often resistant to treatment, may spread to other parts of the body and may be recurrent after they have been removed.
- primary cancer refers to the original, or first, cancer in the body. Cancer cells from a primary cancer may spread to other parts of the body and form new, or secondary, cancers.
- metalastatic cancer refers to a cancer which arises in one organ and only later spreads to other organs.
- the invention relates to a compound of formula (I) or a stereoisomer and/or salt thereof, for use in the treatment and/or prevention of cancer.
- This aspect may also be formulated as a method of treatment and/or prevention of cancer, which comprises administering to a subject in need thereof, including a human, a therapeutically effective amount of a compound of formula (I) or a stereoisomer and/or salt thereof, together with one or more pharmaceutically acceptable excipients or carriers.
- a compound of formula (I) or a stereoisomer and/or salt thereof for the manufacture of a medicament for the treatment and/or prevention of cancer.
- the invention also relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a stereoisomer and/or salt thereof, for use in the treatment and/or prevention of cancer.
- This aspect may also be formulated as a method of treatment and/or prevention of cancer, which comprises administering to a subject in need thereof, including a human, a therapeutically effective amount of the combination comprising a) a compound of formula (I) or a stereoisomer and/or salt thereof, b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents; and one or more pharmaceutically acceptable excipients or carriers.
- the method of treatment and/or prevention of cancer comprises administering to a subject in need thereof, including a human, a single pharmaceutical composition as defined herein, or alternatively, a kit of parts as defined herein.
- a drug combination comprising: a) a compound of formula (I) or a stereoisomer and/or salt thereof, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents, for the manufacture of a medicament for the treatment and/or prevention of cancer.
- the medicament comprises a single pharmaceutical composition as defined herein, or alternatively, a kit of parts as defined herein.
- the treatment and/or prevention of cancer comprises the simultaneous, concurrent, separate or sequential administration of the compound of formula (I) or a stereoisomer and/or salt thereof, and one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
- the present invention also relates to a compound of formula (I), or a stereoisomer and/or salt thereof, for use in combination therapy in the treatment and/or prevention of cancer, wherein the compound of formula (I), or a stereoisomer and/or salt thereof, is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein.
- the invention also relates to one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein for use in combination therapy in the treatment and/or prevention of cancer, wherein the one or more anticancer agents are to be administered simultaneously, concurrently, separately or sequentially with a compound of formula (I), or a salt and/or a stereoisomer thereof.
- the term “simultaneously” as used herein means administering the compound of formula (I) and the anticancer agent or agents at or about the same time.
- the term “concurrently” as used herein means that a dose of a first drug (either the compound of formula (I) or the anticancer agent or agents) is administered prior to the end of the dosing interval of the second drug.
- the term “separately” means administering the compound of formula (I) on the one hand, and the anticancer agent or agents on the other hand, at different times.
- sequentialially means administering in a specific order, where one first drug (either the compound of formula (I) or the anticancer agent or agents) is administered first, and then, the second one is administered after an interval of predetermined time.
- the treatment and/or prevention of cancer is mediated by the inhibition of survivin (FIG. 4).
- the term “inhibition of survivin” as used herein refers to the fact that the compounds of formula (I) or salts and/or stereoisomers thereof, particularly asenapine, are able to block, partially block, interfere, decrease, suppress, reduce or deactivate survivin.
- treatment and/or prevention of cancer mediated by the inhibition of survivin refers to the treatment of cancer which is characterized by an inhibition or downregulation of survivin.
- the cancer is selected from the group consisting of hematological tumors, and solid tumors. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
- the cancer is other than breast cancer
- the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
- asenapine may be of special interest in the treatment of brain tumors, including primary brain tumors or cancers with brain metastases.
- the cancer is selected from the group consisting of lung cancer, more particularly lung adenocarcinoma; colorectal cancer, more particularly colon adenocarcinoma; neuroblastoma, more particularlypediatric neuroblastoma; sarcoma, more particularly pediatric sarcoma, and glioblastoma.
- DMSO dimethyl sulfoxide
- A549 human epithelial adenocarcinoma
- SW620 human colon carcinoma
- HFL-1 normal human lung fibroblast
- U87 human glioblastoma
- LAN-1 human neuroblastoma bone marrow metastasis
- RD pediatric rhabdomyosarcoma
- LLC1 mae Lewis lung carcinoma
- LAN-1 and RD cell lines were cultured in Roswell Park Memorial Institute medium (RPMI, Biological industries) with 100 U/mL penicillin, 100 ug/mL streptomycin and 2 mM L-glutamine and 10% FBS. They all were maintained in a 5% CO2 incubator.
- Dose-response curves of AM, the chemotherapeutics and its combination were developed in order to calculate the inhibitory concentrations (IC) of 25%, 50% and 75% of cell population.
- IC inhibitory concentrations
- cells (10 5 cells/well) were seeded in 96-well microtiter plates and were incubated for 24 h to allow cells to attach. Afterwards, they were treated for 24 h with the compounds.
- concentrations tested were 0.0003-0.04 mg/mL for AM, 0.001- 0.1 mg/mL for cisplatin, 0.008-1 mg/mL for carboplatin, and 0.031-4 mg/mL for gemcitabine.
- the chemotherapeutics and AM were used for the combination experiments, in which 10 5 cells/well were seeded in 96-well microtiter plates. 24 h later, cells were treated with AM, cisplatin /carboplatin /gemcitabine (at the same concentration ranges than before) or AM (0.015 mg/ml_) + cisplatin /carboplatin /gemcitabine.
- SPR assays were designed to monitor the interaction between ligand Survivin (Calmodulin tag; Abcam87202) and the tested compounds.
- Survivin ligand was immobilized following Biacore T200 protocol in a sensor chip CM5 (GE Healthcare BioSciences AB). This is coated with a carboxymethylated dextran matrix that allows a covalent protein attachment by amine coupling.
- CM5 GE Healthcare BioSciences AB
- calmodulin calmodulin
- ligand alone was also immobilized in a channel that would be used as a reference channel. Prior to immobilization, in order to determine the optimal pH to pre-concentrate the ligand over the matrix, a pH scouting was performed prior to immobilization.
- the ligand was diluted to 1 mM in 10 mM acetate buffers with pH 4 and 4.25, and injected during 180 s with a flow of 5 pL/min over an unmodified sensor chip. Then, the surface was regenerated with 50 mM NaOH to ensure no ligand remains bound to the surface. Once the optimum pH was selected, the surface of the sensor chip was activated with a mixture 1:1 of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDO) and N- hydroxysuccinimide (NHS) in order to form reactive ester groups on the surface.
- EEO 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
- NHS N- hydroxysuccinimide
- Survivin protein was diluted to 0.05 pg/pL in 10 mM acetate buffer with pH 4.25 and immobilized in flow-cell 2 up to 1600 RU.
- calmodulin protein was diluted to 0.05 pg/pL in 10 mM acetate buffer with pH 4 and immobilized in flow-cell 1 up to 1300 RU.
- the immobilized ligand level was previously calculated according to the relative molecular weights of the ligand and the analyte and the maximum binding capacity of the surface with a theoretical Rmax (maximal response) of 50 RU. Once the immobilization was performed, ethanolamine solution was injected in order to deactivate the remaining reactive groups of the surface.
- Test compounds were stored as stock solution in 100% DMSO at -20 °C.
- the compounds were diluted with running buffer, 1 x HBS-P (HEPES-buffered saline 0.005% P20) 5% DMSO, at concentrations ranging from 0.012 mM to 40 mM.
- samples were injected in duplicates in both channels at 30 pL/min flow for 90 s and a dissociation time of 300 s.
- a solvent correction with carefully prepared DMSO reference solutions ranging from 4.5% to 5.8% was run.
- Solvent correction was performed to adjust measured sample responses due to solvent effects on the bulk refractive index variations.
- Experiments were performed with the instrument temperature (flow cell, sensor chip, and sample compartment temperature) set to 25 °C.
- Biacore T200 evaluation software 2.0 was used for subtraction of reference and blank data, along with solvent correction as well as for curve fitting, using the 1:1 Langmuir model.
- WCL Whole cell lysate (WCL) from cultured cells was prepared with ice cold lysis buffer containing 0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate, 50 mmol/L sodium fluoride, 40 mmol/L b-glycerophosphate, 200 pmol/L sodium orthovanadate, 1 mmol/L phenylmethylsulfonyl fluoride (all from Sigma-Aldrich), and protease inhibitor cocktail (Roche Diagnostics) in 1X PBS followed by its homogenization using a scrapper. WCL was collected and mixed thoroughly by vortexing with preserved cell death pellet at 4 °C.
- Anti-XIAP 1 1000 Rabbit Cell Signaling Technology Inc. 2045
- Table 1 List of primary antibodies used for Western blot analysis.
- HRP horseradish peroxidase conjugated secondary antibodies diluted 1:5000 in blocking solution for 1 h at RT with shaking.
- the secondary antibodies used were: donkey anti-mouse IgG-HRP (Cat#A16017) and donkey anti-rabbit IgG-HRP (Cat#A16029), both from Thermo Fisher Scientific Inc.
- images were captured on an Image Quant LAS 500 (GE Healthcare) using ECLTM Western blotting detection reagent (Cat#RPN2106, Amersham, GE Healthcare, Buckinghamshire, UK). Band densitometries were retrieved using the Image Studio Lite software (v5.2, LI-COR Biosciences). GAPDH was used as gel loading control. The results shown are representative of Western blot data analysis obtained from at least three independent experiments.
- mice In AM toxicity assay, ten-week-old mice were separated in 4 different groups (4 mice/group): vehicle (7.5% DMSO and 0.8% Tween20 in PBS), 10 mg/kg, 15 mg/kg and 20 mg/kg AM treated. The treatment was intraperitoneally injected once a day in a 5-days- on/2-days-off schedule. Body weight was recorded daily until the end of the treatment. Once mice were sacrificed, blood, liver, kidneys, spleen and brain were extracted and weighted. Organs were fixed in 4% paraformaldehyde (PFA) at 4 °C for 24 h. Then, the samples were processed for hematoxylin and eosin (HE) staining and were analyzed on the microscope.
- PFA paraformaldehyde
- AM efficacy assay and combination efficacy assay a subcutaneous mice model was used and 100 pL of 5-10 4 LLC1 cells in PBS:Matrigel (Corning) (1:1) were inoculated into the mice right flank.
- PBS:Matrigel (Corning) (1:1) were inoculated into the mice right flank.
- tumor-bearing mice were separated into 2 groups and treated with vehicle or 10 mg/kg of AM once a day on a 5- days-on/2-days-off schedule for 22 days for the AM therapeutic assay.
- mice were treated with AM (5 mg/kg, 5 days per week), cisplatin (3 mg/kg days 0, 3 and 6), AM plus CisPt in combination or vehicle. Body weight and tumor volume were daily recorded.
- Tumor volume was calculated by following formula: width 2 x length/2. Mice were sacrificed and tumors were extracted and weighted. Tumors were kept in PBS until all of them were collected and then they were photographed. Tumors were fixed in 4% PFA at 4°C. After 24 h, samples were processed for HE staining and were analyzed on the microscope.
- A549 and SW620 cells were treated at different concentrations (in a range between 0.8 and 100 pM) for 24 h.
- AM can easily cross the blood-brain barrier, due its tetracyclic structural nature, it was also considered of interest evaluating the cytotoxic effect of AM on the glioblastoma cell line U87, for its possible application in the treatment of brain cancers and brain metastasis.
- pediatric neuroblastoma and sarcoma cells were also evaluated after AM treatment, since they are malignancies with limited successful treatments approved. Experiments were carried out in triplicates. Results are shown in FIG. 2.
- analytes AM and Abbott23b were injected in solution as well as in duplicates over the sensor surface at concentrations ranging from 0.012 to 40 mM.
- Abbott23b was used as a positive control due to its already described high capacity to interact with the dimer interface of survivin.
- Changes in SPR response were collected and analyzed using the Biacore T200 Evaluation Software, included in the system. These changes, expressed in response units (RU), showed the association and dissociation curves of the interactions among survivin and the analytes AM and Abbott23b (FIG. 3 A), allowing in turn to obtain the affinity curves (FIG. 3 B).
- the data collected showed a binding constant (KD) in the low micromolar range.
- a subcutaneous tumor model C57BL/6 mice inoculated with mouse Lewis lung carcinoma cell line (LLC1), was used to test the efficacy of AM in combination with the chemotherapeutic agent cisplatin.
- AM and/or cisplatin were intraperitoneally administered at 5 mg/kg AM (5 days per week), 3 mg/kg cisplatin (Days 0, 3 and 6), AM plus CisPt in combination or vehicle (V).
- Mice weight was monitored during treatment and represented as difference of weight (W), in percentage, respect to initial weight. Tumor volume was also monitored during the experiment and tumor weight was assessed at the end of the experiment. Results are shown in FIG. 11.
- Clause 2 The compound for use according to clause 1 , wherein the compound of formula (I) is in the form of a salt which is asenapine maleate.
- a pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in any of clauses 1-2, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
- Clause 4. The compound for use according to any of clauses 1-2, or the pharmaceutical composition for use according to clause 3, wherein the treatment and/or prevention of cancer is mediated by the inhibition of survivin.
- Clause 5 The compound or composition for use according to any of clauses 1-4, wherein the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
- the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma
- Clause 6 The compound or composition for use according to any of clauses 1-5, wherein the cancer is other than breast cancer, more particularly the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
- the cancer is other than breast cancer, more particularly the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer,
- Clause 7 The compound or composition for use according to any of clauses 1-6, wherein the cancer is lung cancer, more particularly lung adenocarcinoma.
- Clause 8 The compound or composition for use according to any of clauses 1-6, wherein the cancer is colorectal cancer, more particularly colon adenocarcinoma.
- Clause 9 The compound or composition for use according to any of clauses 1-6, wherein the cancer is neuroblastoma, more particularly pediatric neuroblastoma.
- Clause 10 The compound or composition for use according to any of clauses 1-6, wherein the cancer is sarcoma, more particularly pediatric sarcoma.
- Clause 11 The compound or composition for use according to any of clauses 1-6, wherein the cancer is glioblastoma.
- a drug combination comprising: a) compound as defined in any of clauses 1-2, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents and hormone therapy agents, more particularly the anticancer agents are chemotherapy agents.
- Clause 13 The drug combination according to clause 12, which comprises a) compound as defined in any of clauses 1-2, and b) one anticancer agent selected from the group consisting of chemotherapy agents, immunotherapy agents and hormone therapy agents.
- Clause 14 The drug combination according to clause 12, which comprises a) compound as defined in any of clauses 1-2, and b) two anticancer agents, which may belong to the same or to a different class, selected from the group consisting of chemotherapy agents, immunotherapy agents and hormone therapy agents.
- Clause 15 The drug combination according to clause 13, wherein the anticancer agent is a chemotherapy agent.
- the chemotherapy agent is an antimetabolite, more particularly wherein the antimetabolite is selected from the group consisting of antifolates, pyrimidine antagonists, purine antagonists, and ribonucleotide reductase inhibitors; even more particularly wherein the antimetabolite is selected from the group consisting of methotrexate, pemetrexed, cytarabine, 5-fluorouracil (5-FU), capecitabine, gemcitabine, 6-mercaptopurine (6-MP), azathioprine, fludarabine, cladribine, and hydroxyurea.
- the antimetabolite is selected from the group consisting of antifolates, pyrimidine antagonists, purine antagonists, and ribonucleotide reductase inhibitors; even more particularly wherein the antimetabolite is selected from the group consisting of methotrexate, pemetrexed, cytarabine, 5-fluorouracil (5-FU), capecitabine,
- the chemotherapy agent is an alkylating agent, more particularly wherein the alkylating agent is selected from the group consisting of an oxazaphosphorine, nitrogen mustard, an imidazotetrazine, a nitrosourea, an alkyl sulfonate, a hydrazine, and a platinum-based agent; even more particularly wherein the alkylating agent is selected from the group consisting of cyclophosphamide, ifosfamide, chlorambucil, melphalan, temozolomide, carmustine, lomustine, streptozocin, busulfan, procarbazine, cisplatin, carboplatin, and oxaliplatin.
- the alkylating agent is selected from the group consisting of an oxazaphosphorine, nitrogen mustard, an imidazotetrazine, a nitrosourea, an alkyl sulfonate, a hydrazine, and a platinum-based agent;
- the chemotherapy agent is a topoisomerase inhibitor, more particularly wherein the topoisomerase inhibitor is selected from the group consisting of a topoisomerase I inhibitor, and a topoisomerase II inhibitor; even more particularly wherein the topoisomerase inhibitor is selected from the group consisting of irinotecan, topotecan, etoposide, and teniposide.
- the chemotherapy agent is a topoisomerase inhibitor, more particularly wherein the topoisomerase inhibitor is selected from the group consisting of a topoisomerase I inhibitor, and a topoisomerase II inhibitor; even more particularly wherein the topoisomerase inhibitor is selected from the group consisting of irinotecan, topotecan, etoposide, and teniposide.
- the chemotherapy agent is a mitotic inhibitor, more particularly wherein the mitotic inhibitor is selected from the group consisting of a vinca alkaloid, a taxane, and a nontaxane microtubule inhibitor; even more particularly wherein the mitotic inhibitor is selected from the group consisting of vincristine, vinblastine, vinorelbine, docetaxel, paclitaxel, eribulin, ixabepilone, and epothilone.
- the chemotherapy agent is an antitumor antibiotic, more particularly wherein the antitumor antibiotic is selected from the group consisting of bleomycin, actinomycin D, doxorubicin, daunorubicin, idarubicin, and mitomycin.
- the chemotherapy agent is a protein kinase inhibitor, more particularly wherein the protein kinase inhibitor is selected from the group consisting of a BCR-ABL tyrosine kinase inhibitor, a c-KIT tyrosine kinase inhibitor, an EGFR tyrosine kinase inhibitor, an ALK tyrosine kinase inhibitor, a V600E mutated-BRAF oncogene inhibitor, a MEK inhibitor, a Bruton tyrosine kinase inhibitor, a Janus kinase inhibitor, and a CDK inhibitor; even more particularly wherein the protein kinase inhibitor is selected from the group consisting of imatinib, dasatinib, nilotinib, erlotinib, gefitinib, afatinib, Osimertinib, alectinib, crizot
- the chemotherapy agent is a proteasome inhibitor, more particularly wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib.
- Clause 26 The drug combination according to clause 13, wherein the anticancer agent is an immunotherapy agent.
- Clause 27 The drug combination according to clause 26, wherein the immunotherapy agent is an immune checkpoint inhibitor, more particularly wherein the immune checkpoint inhibitor is selected from the group consisting of ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.
- Clause 28 The drug combination according to clause 26, wherein the immunotherapy agent is selected from the group consisting of an interferon, an interleukin, an oncolytic virus, a cytokine, and a chimeric antigen receptor T cell (CAR-T) product.
- the immunotherapy agent is selected from the group consisting of an interferon, an interleukin, an oncolytic virus, a cytokine, and a chimeric antigen receptor T cell (CAR-T) product.
- Clause 29 The drug combination according to clause 13, wherein the anticancer agent is a hormone therapy agent.
- the hormone therapy agent is an aromatase inhibitor, more particularly wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole.
- the hormone therapy agent is an anti-androgen, more particularly wherein the anti-androgen is selected from the group consisting of apalutamide, enzalutamide, darolutamide, bicalutamide, flutamide, and nilutamide.
- the hormone therapy agent is a CYP17 inhibitor, more particularly wherein the CYP17 inhibitor is abiraterone or ketoconazole.
- the hormone therapy agent is a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, more particularly wherein the luteinizing hormone-releasing hormone (LHRH) agonist or antagonist is selected from the group consisting of goserelin, leuprolide, triptorelin, and degarelix.
- Clause 37 The drug combination according to clause 29, wherein the hormone therapy agent is an adrenolytic, more particularly wherein the adrenolytic is mitotane.
- Clause 38 The drug combination according to clause 12, which comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) cisplatin.
- Clause 40 The drug combination according to clause 12, which comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) gemcitabine.
- a single pharmaceutical composition which comprises: a) a therapeutically effective amount of a compound as defined in any of clauses 1-2; and b) a therapeutically effective amount of one or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy agents as defined in any of clauses 15-37; and one or more pharmaceutically acceptable excipients or carriers.
- kits of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound in any of clauses 1-2, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy agents as defined in any of clauses 15-37, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions.
- Clause 43 A drug combination as defined in any of clauses 12-40, a single pharmaceutical composition as defined in clause 41, or a kit of parts as defined in clause 42, for use in the treatment and/or prevention of cancer.
- Clause 44 The drug combination for use according to clause 43, wherein the treatment and/or prevention of cancer is mediated by the inhibition of survivin.
- the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
- Clause 46 The drug combination for use according to any of clauses 43-45, wherein the cancer is other than breast cancer, more particularly the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
- lymphoma pancreatic cancer
- stomach cancer liver cancer
- bladder cancer cervical cancer
- ovarian cancer colorectal cancer
- colon cancer mesothelioma
- urothelial cancer esophageal cancer
- melanoma myeloma
- prostate cancer renal cancer
- lung cancer sarcoma
- brain cancer neuroblastoma
- neuroblastoma
- Clause 47 The drug combination for use according to any of clauses 43-46, wherein the cancer is lung cancer, more particularly lung adenocarcinoma.
- Clause 48 The drug combination for use according to any of clauses 43-46, wherein the cancer is colorectal cancer, more particularly colon adenocarcinoma.
- Clause 49 The drug combination for use according to any of clauses 43-46, wherein the cancer is neuroblastoma, more particularly pediatric neuroblastoma.
- Clause 50 The drug combination for use according to any of clauses 43-46, wherein the cancer is sarcoma, , more particularly pediatric sarcoma.
- Clause 51 The drug combination for use according to any of clauses 43-46, wherein the cancer is glioblastoma.
- Clause 52 A compound as defined in any of clauses 1-2, for use in combination therapy in the treatment and/or prevention of cancer, wherein the compound is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy agents as defined in any of clauses 15-37; more particularly wherein the cancer is as defined in any of the clauses 44-51.
Abstract
It relates to a compound of formula (I), particularly asenapine, or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its pharmaceutically acceptable salts, for use in the treatment and/or prevention of cancer. It also relates to a drug combination of a compound of formula (I), its stereoisomers and/or salts thereof, and one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents; and to pharmaceutical compositions and to a kit of parts comprising this combination, as well as the use of the drug combination, the compositions, or kit of parts for use in the treatment and/or prevention of cancer.
Description
Asenapine for use in cancer
This application claims the benefit of the European Patent Application 21382721.5 filed on 30.07.2021.
TECNICAL FIELD
The present invention relates to the therapeutical indication of asenapine in cancer. It also relates to drug combinations of asenapine and other anticancer agents, as well as to pharmaceutical compositions and kits containing them, and to the use of the latter in medicine, in particular as anticancer agents.
BACKGROUND ART Cancer is the second leading cause of death worldwide, accounting for an estimated almost 10.0 million deaths in 2020, and the number of cancer patients has increased year by year. The most common types of cancer in men are lung, prostate, colorectal, stomach and liver cancer, while among women breast, colorectal, lung, cervical and thyroid cancer are the most common. Cancer is currently treated by a number of methods including surgery, radiotherapy, chemotherapy and molecular-targeted therapy.
Lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women. Lung cancer is by far the leading cause of cancer death among both men and women, making up almost 25% of all cancer deaths. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined.
Brain and central nervous system (CNS) cancers represent around 1.7% of the total cancer cases and are two of the primary cancers that affect children and young adults. In children, brain cancers including for example neuroblastoma are the most common solid tumor and the leading cause of death from cancer among children.
On the other hand, gliomas, which represent 45 - 55% of all primary cerebral tumors, are the most common of the CNS tumors. Glioblastoma is an aggressive glioma that is notoriously difficult to treat due to its diffuse infiltration into surrounding tissue. Conventional treatment of brain tumors include surgery, radiation therapy and chemotherapy. Despite improvements in surgery techniques and therapeutic protocols, patients with this type of cancers usually often show poor prognosis. Besides,
chemotherapeutic efficacy in brain tumors is limited by toxic effects on healthy cells and also by the ability of the drugs to cross the blood-brain barrier (BBB).
Cancer is a heterogeneous group of diseases that results not just from aberrant cellular proliferation but also from lack of well-regulated cell death. Resistance to apoptosis is one important evasion mechanism by which tumor cells may present chemoresistance and thus contribute to cancer progression. Consequently, molecules involved in regulation of apoptosis are considered potential targets for cancer therapy. Survivin is a small protein that belongs to the inhibitor of apoptosis (IAP) protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in many human neoplasms. Overexpression of survivin has been strongly associated with inhibition of the intrinsic and extrinsic cell death pathway. Survivin also seems to play an important role in cell division. Consequently, aberrant survivin expression stimulates tumor progression and confers resistance to several therapeutic strategies in a variety of tumors. In fact, efficient survivin downregulation or inhibition results in spontaneous apoptosis or sensitization to chemotherapy and radiotherapy. Therefore, all these features make survivin an attractive therapeutic target to treat cancer.
Currently, there are several survivin inhibitors under development, yet still no survivin- specific anticancer agent has reached the market up to date. In fact, the most advanced survivin inhibitors, the survivin antisense oligonucleotide LY2181308, and the small molecule YM155, were discontinued after multiple clinical trials due to either low antitumor efficacy and/or over toxicity issues possibly due to insufficient target inhibition or selectivity.
Antipsychotic drugs are commonly classified into two different groups: typical antipsychotics, also known as first-generation antipsychotics (FGAs), and atypical antipsychotics, also known as second-generation antipsychotics (SGAs). While FGAs have been classified according to their chemical structure, SGAs are grouped by their pharmacological properties. SGAs’ mechanisms of action and side-effects differ significantly from drug to drug. Asenapine is the generic name of the chemical compound 5-chloro-2-methyl-2,3,3a,12b- tetrahydrodibenzo[2,3:6,7]oxepino[4,5-c]pyrrole. Asenapine is a trans-racemate composed by a mixture of the following enantiomers:
Asenapine is an atypical antipsychotic sold in the form of its maleate salt under the brand name Saphris, among others. It is used to treat schizophrenia and acute mania associated with bipolar disorder. Asenapine, as well as processes for its preparation, were described for the first time in US4145434.
To the best knowledge of the inventors no experimental data supporting the use of asenapine in cancer have been reported so far. In the few publications which disclose asenapine and cancer, either no relevant experimental data are included, or it is concluded that asenapine has no activity in cancer.
For example, the Chinese patent application WO2016062285 discloses anticancer compositions containing drugs used for treating nervous system diseases. Asenapine is mentioned as an example of this class of drugs. Table 3 reports data on the inhibition of asenapine among a very long list of other active agents against the following cancer cell lines: H1650 (lung adenocarcinoma), A549 (lung adenocarcinoma), AGS (gastric adenocarcinoma), MKN-45 (gastric adenocarcinoma), HepG2 (Hepatocellular carcinoma), HCT116 (colorectal carcinoma), LoVo (colorectal adenocarcinoma), A375 (amelanotic melanoma), HeLa (cervix adenocarcinoma), PC3 (prostate adenocarcinoma), TSGH-8301 (urinary bladder carcinoma), MCF7 (mammary Gland adenocarcinoma), and HL-60 (acute promyelocytic leukemia). Drugs with a significant effect against any of the tested cancer cell lines seem to be grey-shaded. This is not the case of asenapine. In fact, it is disclosed that in accordance with the results of table 3, a repetitive experiment was performed for the effective drugs, whose results are reported in Table 4. Asenapine is not among these active agents listed in table 4. Further, the inventors of WO2016062285 disclose in table 2 a list of drugs without any inhibitory effects on the cancer cell lines. Asenapine is included in this table with an “inhibition value” of 0.
Further, Zhang W. et al. (Sci Rep 2018 Oct 25;8(1): 15753) discloses that FGAs have been explored as agents against untreatable brain metastases because of their ability to cross the blood-brain barrier (BBB), but that they have shown limited clinical application because FGAs are associated with a spontaneous death risk, especially in elderly patients. Zhang et al. investigated antitumor activities of eight SGAs, including asenapine,
toward a breast cancer (TNBC) cell line. However, the authors reported that asenapine was only slightly more effective than positive control clozapine, and discarded asenapine as well all the tested compounds except sertindole for carrying out further anticancer studies.
On the other hand, EP3708161 discloses the use of 6 compounds for preventing or treating a disease or symptom caused by mitochondrial dysfunction. These compounds include an anti-Parkinson agent (compound 1-1), 3 FGAs (compounds I-4, I-5, and I-6), and 2 SGAs including olanzapine (compound I-3) and asenapine (compound I-2). Cancer is cited among the list of diseases or symptoms caused by mitochondrial dysfunction. However, there is no single experimental data in the patent application which supports any potential use of these compounds in cancer. Rather, the only experimental data provided for asenapine maleate (compound 1-2-1, also referred to as compound 105), as well as for the other compounds, relates to efficacy in fibroblasts from patients with MELAS and Leigh syndrome, which are neurological disorders not related to cancer.
Moreover, none of the above documents disclose or suggest the treatment of cancer mediated by the inhibition of survivin. There is still a need to find further therapies for the treatment of cancer which sensitize to conventional therapies, reduce chemotherapy resistance and show improved efficacy in order to improve patients’ quality of life as well as overall survival.
SUMMARY OF INVENTION
The present inventors found that asenapine may be effectively used in the treatment of cancer. Despite the teachings of the prior art which disclosed that asenapine did not show any inhibitory effects on cancer cell lines (WO2016062285) or discarded asenapine for further testing against cancer based on the available results (Zhang W. et al.), it is herein demonstrated that asenapine is not only able to show moderate anticancer activity against several cancer cell lines in vitro, but also antitumoral effects in vivo.
In particular, as illustrated in the examples below, asenapine reduced the cell viability in lung adenocarcinoma (A549), and colon adenocarcinoma (SW620) cancer cell lines with statistical significance, while not being cytotoxic to healthy cells (FIG. 1). Asenapine also showed in vitro anticancer effects against pediatric neuroblastoma (LAN-1), pediatric sarcoma (RD), and glioblastoma (U87) (FIG. 2) in the same range of efficacy as other approved chemotherapeutics such as cisplatin.
Additionally, asenapine also showed antitumoral activity in vivo in a subcutaneous tumor mice model of lung carcinoma (FIG. 7, 8). Importantly, when tested in mice the administration of asenapine at doses of 10, 15 and 20 mg/kg did not show any significant toxicity, it did not affect mice growth (FIG. 5) nor organs weight (FIG. 6).
Apart from the potential use of asenapine as monotherapy against cancer, asenapine may be advantageously used in combination with classical chemotherapeutic agents or other anticancer agents and provide an improved treatment thanks to a synergistic anticancer effect attained by the drug combination. In this regard, the inventors have found that combinations of asenapine with chemotherapeutic agents of different nature, such as cisplatin, carboplatin, and gemcitabine acted synergistically against cancer in vitro and in vivo (FIG. 9, FIG. 10 and FIG. 11). The fact that the drug combinations of the invention show synergistic effects may allow the use of lower dosages of one or more of the therapeutic agents of the combination, and/or less frequent administration of the drugs. As a consequence, the use of these drug combinations may lead to a reduction of potential adverse side-effects, which is highly desirable for improving the quality of life of the patients, but without reducing the efficacy of the therapy.
Without being bound to theory it is thought that asenapine’s role in the treatment of cancer could be related to its ability to inhibit survivin. As stated before, the main established functions of survivin are the regulation of cell mitosis and the inhibition of apoptosis. The present inventors found that asenapine shows high affinity to the ligand survivin (FIG. 3) and, in particular, is able to specifically inhibit survivin protein levels (FIG. 4). This mechanism was unknown so far to the best knowledge of the inventors. Thus, through its survivin inhibitory action it is postulated that asenapine would be able to i) induce apoptosis in tumor cells; ii) inhibit cell cycle; and iii) sensitize tumor cells to standard chemotherapeutic agents or other anticancer agents, without being toxic to healthy cells.
Therefore, a first aspect of the invention relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its salts
for use in the treatment and/or prevention of cancer.
A second aspect of the invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
As mentioned above, asenapine sensitizes tumor cells to standard chemotherapeutic agents. Therefore, a third aspect of the invention relates to a drug combination comprising: a) compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its salts, as defined herein, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
The drug combinations of the invention may be formulated in different types of compositions or kits of parts for use together. Thus, a fourth aspect of the invention relates to a single pharmaceutical composition which comprises: a) a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein; b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein; and one or more pharmaceutically acceptable excipients or carriers.
A fifth aspect of the invention relates to a kit of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound of
formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions. Further, as previously indicated, the drug combinations of the invention may be used in cancer. Thus, a sixth aspect of the invention relates to the drug combination, the single pharmaceutical composition, or the package or kit of parts as defined herein, for use in the treatment and/or prevention of cancer. A seventh aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts, for use in combination therapy in the treatment and/or prevention of cancer, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein, is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein.
An eighth aspect of the invention relates to one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents for use in combination therapy in the treatment and/or prevention of cancer, wherein the one or more anticancer agents are to be administered simultaneously, concurrently, separately or sequentially with a compound of formula (I), or a pharmaceutically acceptable salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of its pharmaceutically acceptable salts as defined herein. BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows the percentage of MTT cell viability (%V) after 24 h of treatment with asenapine at 5 and 20 mM in normal human lung fibroblast (HFL-1), lung adenocarcinoma
(A549) and colon adenocarcinoma (SW620) with respect to control (Ctl). Bars represent the mean ± SD. Statistically significant results are indicated as *, p-value < 0.05; **, p- value < 0.01 and ***, p-value < 0.001. FIG. 2 shows the percentage of MTT cell viability (%V) after 24 h of treatment with AM at concentrations ranging from 0.8 to 100 mM in lung adenocarcinoma (A549), colon adenocarcinoma (SW620), pediatric neuroblastoma (LAN-1), pediatric sarcoma (RD), and glioblastoma (U87) cancer cell lines. Results are shown as mean ± SD. FIG. 3 shows binding to survivin of AM and Abbot23b. A, Association and dissociation experimental curves for binding (concentrations of Abbot23b and AM ranging from 0.012 to 40 pM) to immobilized survivin (Calmodulin tag) analyzed by SPR. B, Affinity curves data. RU: Response units; t(s): time in seconds; (M): concentration in molar. FIG. 4 shows the decrease of survivin levels in cells in vitro treated with AM with respect to control (Ctl). After 24 h of treatment with IC50 value of AM, the expression of survivin and XIAP was analyzed by Western blot analysis in A549 cell line. Protein levels were normalized with their respective loading controls. (F.C. = fold change). Bars represent the mean ± SD. Statistically significant results are indicated as *, p-value < 0.05; **, p-value < 0.01 and ***, p-value < 0.001.
FIG. 5 shows the mice growth (%W) during the toxicity study as difference of weight in percentage respect to initial weight, after treating mice with 10, 15 and 20 mg/kg of AM or vehicle (V) for 5 days per week. Results are shown as mean ± SEM. t (d): time in days.
FIG. 6 shows the organs weight during the toxicity as percentage of mice weight after treating mice with 10, 15 and 20 mg/kg of AM or vehicle (V) for 5 days per week. Results are shown as mean ± SD. 0= organs, T.W.= total weight, K= kidneys, L= liver, S= spleen, B= brain.
FIG. 7 shows the mice growth (%W) during the efficacy study as difference of weight in percentage respect to initial weight after treating C57BL/6 mice, inoculated with mouse Lewis lung carcinoma cell line (LLC1), with 10 mg/kg of AM or vehicle (V) for 5 days per week. Results are shown as mean ± SEM. t (d): time in days.
FIG. 8 shows the tumor volume (T.V.) during the efficacy assay after treating C57BL/6 mice, inoculated with mouse Lewis lung carcinoma cell line (LLC1), with 10 mg/kg of AM or vehicle (V). Results are shown as mean ± SEM. t (d): time in days.
FIG. 9 shows the MTT assay performed after 24 h of treatment with AM or AM plus a chemotherapeutic (cisplatin (CisPt), or carboplatin (CbPt)) in lung adenocarcinoma (A549). A, IC50 value of the chemotherapeutic alone versus IC50 of the combination. B, Percentage of cell viability (V) alone (CisPt 0.1 mg/ml_, CbPt 0.25 mg/ml_) or in combination treatment. C, fractional inhibition (FA) of the chemotherapeutic and the combined treatment. D, combination index (Cl) of the treatment at different concentrations of chemotherapeutics. Synergism: Cl= 0.30-0.70, moderate synergism: Cl= 0.70-0.85, slight synergism: Cl= 0.85-0.90, nearly additive: Cl= 0.9-1.1. Bars represent the mean ± SD. Statistically significant results are indicated as *, p-value < 0.05; **, p-value < 0.01;
***, p-value < 0.001 and ****, p-value < 0.0001.
FIG. 10 shows the MTT assay performed after 24 h of treatment with AM or AM plus a chemotherapeutic (gemcitabine (Gem)) in lung adenocarcinoma (A549). A, IC50 value of the chemotherapeutic alone versus IC50 of the combination. B, Percentage of cell viability (V) alone (4 mg/ml_) or in combination treatment. C, fractional inhibition (FA) of the chemotherapeutic and the combined treatment. D, combination index (Cl) of the treatment at different concentrations of chemotherapeutics. Synergism: Cl= 0.30-0.70, moderate synergism: Cl= 0.70-0.85, slight synergism: Cl= 0.85-0.90, nearly additive: Cl= 0.9-1.1. Bars represent the mean ± SD. Statistically significant results are indicated as *, p-value < 0.05; **, p-value < 0.01; ***, p-value < 0.001 and ****, p-value < 0.0001.
FIG. 11 shows the therapeutic effect of AM and AM in combination with cisplatin (CisPt).
A) shows mice growth (%W) during the combination efficacy study as difference of weight (in percentage) respect to initial weight, after treating C57BL/6 mice subcutaneously inoculated with mouse Lewis lung carcinoma cell line (LLC1), with AM (5 mg/kg, 5 days per week), cisplatin (3 mg/kg on days 0, 3 and 6), AM plus CisPt in combination or vehicle (V). B) shows the tumor volume (T.V.) during the combination efficacy assay after treating C57BL/6 mice subcutaneously inoculated with LLC1 cells, with AM, CisPt, CisPt+AM or vehicle. C) shows tumor weight (T.W.) at the end of the combination efficacy assay after treating C57BL/6 mice subcutaneously inoculated with LLC1 cells, with AM, CisPt, CisPt+AM or vehicle. Results are shown as mean ± SEM. t (d): time in days. **p<0.01. Statistical analysis was subjected to One-way ANOVA test, with Tukey test for multiple comparisons.
DESCRIPTION OF EMBODIMENTS
All terms as used herein in this application, unless otherwise stated, shall be understood
in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.
The term "about" or “around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or “around 10” includes ± 10% of 10, i.e. from 9 to 11. The compounds of formula (I)
As mentioned above, the invention relates to a compound of formula (I) or a stereoisomer and/or a salt thereof, for use in the treatment and/or prevention of cancer.
The compound of formula (I) has two chiral centres that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric isomers (cis/trans or syn/anti), and isomers that are not mirror images of one another (diastereoisomers). The present invention relates to each of these stereoisomers and also to mixtures thereof.
Diastereoisomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be individually obtained using enantiospecific synthesis or can be resolved by conventional techniques of optical resolution to give optically pure isomers.
There is no limitation on the type of salt of the compound of formula (I) that can be used, provided that these are pharmaceutically acceptable when they are used for therapeutic purposes. The term "pharmaceutically acceptable salts", embraces non-toxic salts commonly used. The preparation of pharmaceutically acceptable salts of the compound of formula (I) can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic moiety, by reacting it with a stoichiometric amount of an appropriate pharmaceutically acceptable inorganic or organic acid, in water or in an organic solvent or in a mixture of them. The compound of formula (I) and its salts may differ in some physical properties, but they are equivalent for the purposes of the present invention.
Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula
(I) which can be used for the purposes of the present invention include acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, lactate, maleate, oxalate, fumarate. tartrate, malate, citrate, nicotinate, benzoate, salicylate, pamoate, hemipamoate, ascorbate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, camphorsulfonate, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, hydrogenphosphate, dihydrogenphosphate, carbonate, hydrogencarbonate, perchlorate, aspartate or glutamate.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) is in the form of its maleate salt.
The compound of formula (I) or its stereoisomers and/or salts may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates). All these forms are within the scope of the present invention. Methods of solvation are generally known within the art. In general, the solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention. In all embodiments of the invention referring to the compound of formula (I), its pharmaceutically acceptable salts thereof as well as the stereoisomers or mixtures of stereoisomers, either of any of the compound of formula (I), or of any of its pharmaceutically acceptable salts, are always contemplated even if they are not specifically mentioned.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) is selected from the group consisting of a compound of formula (la), a compound of (lb), a racemic mixture of a compound of formula (la) and a compound of (lb), and a pharmaceutically acceptable salt of any of them
(la) (lb).
More particularly, the compound of formula (I) is a racemic mixture of a compound of formula (la) and a compound of (lb), or a pharmaceutically acceptable salt thereof.
According to one embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) is asenapine, more particularly asenapine maleate.
Anticancer agents As mentioned previously, the invention also relates to a drug combination comprising a) compound of formula (I) or a stereoisomer and/or a salt thereof as defined herein, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the drug combination comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) one or more chemotherapy agents. The term "one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents", as used herein, refers to exactly one but also to more than one, such as two, three, and so on. The term "one or more" does not define the actual number of one type of anticancer agent but refers to the number of distinct molecules of the recited class.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the drug combination comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) one anticancer agent selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents, more particularly one chemotherapy agent.
In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the drug combination comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) two anticancer agents, which may belong to the same or to a different class, selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
As used herein, the term "chemotherapy or chemotherapeutic agent" refers to cytotoxic, cytostatic, and antineoplastic agents that preferentially kill, inhibit the growth of, or inhibit the metastasis of neoplastic cells or disrupt the cell cycle of rapidly proliferating cells.
As chemotherapy agents, the following may be used: antimetabolites, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antitumor antibiotics, protein kinase inhibitors, enzymes, proteasome inhibitors, PARP inhibitors, histone deacetylase inhibitors. The term “antimetabolites” in the context of the invention refers to compounds that are functionally distinct but structurally similar to, biological components involved in growth regulating biochemical reactions, called metabolites. Antimetabolites block cell division and inhibit growth related pathways by replacing required biological components (metabolites) and preventing their functioning. Non-limiting examples of antimetabolites include antifolates, such as methotrexate, and pemetrexed; pyrimidine antagonists such as cytarabine, 5-fluorouracil (5-FU), capecitabine, and gemcitabine; purine antagonists, such as 6-mercaptopurine (6-MP), azathioprine, fludarabine, and cladribine; or ribonucleotide reductase inhibitors, such as hydroxyurea. The term “alkylating agents” as used herein refers to any antineoplastic compound that irreversibly binds to a variety of susceptible biomolecules such as nucleic acids, proteins, amino acids, and nucleotides, in particular DNA. This covalent interaction mediates cell death through interference with DNA structure and function, inactivation of DNA repair enzymes, or cell membrane damage. The term “platin compounds” refers to alkylating agents which are coordination complexes of platinum that bind DNA, resulting in ineffective DNA damage repair and, ultimately, the death of the cancer cell. Non-limiting examples of alkylating agents include oxazaphosphorines, such as cyclophosphamide and ifosfamide; nitrogen mustards, such as chlorambucil and melphalan; imidazotetrazines, such as temozolomide; nitrosoureas, such as carmustine, lomustine, and streptozocin; alkyl sulfonates, such as busulfan; hydrazines, such as procarbazine; or platinum-based agents, such as cisplatin, carboplatin, and oxaliplatin.
As used herein, “topoisomerase inhibitors” refer to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of topoisomerase enzymes, including topoisomerase I and topoisomerase II. Non-limiting examples of topoisomerase inhibitors include topoisomerase I inhibitors, such as irinotecan, and topotecan; and topoisomerase II inhibitors, such as etoposide, and teniposide.
The term "mitotic inhibitor" as used herein refers to compounds which inhibit mitosis or cell division by disrupting microtubules. Non-limiting examples of mitotic inhibitors include vinca alkaloids, such as vincristine, vinblastine, and vinorelbine; taxanes, such as docetaxel, and paclitaxel; or nontaxane microtubule inhibitors, such as eribulin, ixabepilone, and epothilone.
The term "antitumor antibiotics" as used herein refer to antibiotics having antitumor activity, and includes substances that inhibit the growth or other functions of cells in microorganisms or other organisms. Non-limiting examples of antitumor antibiotics include bleomycin, actinomycin D, anthracyclines, such as doxorubicin, daunorubicin, and idarubicin; or mitomycin.
As used herein, “kinase inhibitors” refers to compounds that totally or partially reduce, inhibit, interfere with or modulate the action of one or more protein kinases. Non-limiting examples of protein kinase inhibitors include BCR-ABL tyrosine kinase inhibitors and c- KIT tyrosine kinase inhibitors, such as imatinib, dasatinib, and nilotinib; EGFR tyrosine kinase inhibitors, such as erlotinib, gefitinib, afatinib, and osimertinib; ALK tyrosine kinase inhibitors, such as alectinib, and crizotinib; V600E mutated-BRAF oncogene inhibitors, such as dabrafenib, vemurafenib, and encorafenib; MEK inhibitors, such as trametinib; Bruton tyrosine kinase inhibitors, such as ibrutinib; Janus kinase inhibitors, such as ruxolitinib; or CDK inhibitors, such as palbociclib.
The term “proteasome inhibitors” as used herein refers to compounds that totally or partially reduce, inhibit, interfere with or modulate at least one enzymatic activity of the proteasome. These compounds prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro- apoptotic pathways. Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, and ixazomib.
The term "PARP inhibitor" as used herein refers to an inhibitor or antagonist of poly(ADP- ribose) polymerase activity. PARP inhibitors include compounds which specifically inhibit a particular PARP protein or proteins, such as PARP1 and/or PARP2. Non-limiting examples of PARP inhibitors include olaparib.
The term "histone deacetylase inhibitor" as used herein refers to a compound that selectively targets, decreases, or inhibits at least one activity of a histone deacetylase. Non-limiting examples of Histone deacetylase inhibitors include vorinostat and romidepsin.
Non-limiting examples of enzymes include L-asparaginase.
The term “hormone therapy agents” in the context of the invention refers to proteins or substances that help to control cancers depend on hormones to grow. Treating cancer with hormones is called hormone therapy, hormonal therapy, or endocrine therapy. Hormone therapy is mostly used to treat certain kinds of breast cancer and prostate cancer that depend on sex hormones to grow. Non-limiting examples of hormone therapy include aromatase inhibitors (Als), such as anastrozole, exemestane, and letrozole; selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene; estrogen receptor antagonists, such as fulvestrant and toremifene; anti-androgens, such as apalutamide, enzalutamide, darolutamide, bicalutamide, flutamide, and nilutamide; CYP17 inhibitors, such as abiraterone and ketoconazole; luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, such as goserelin, leuprolide, triptorelin, and degarelix; progestins, such as medroxyprogesterone acetate or megestrol acetate; or adrenolytics, such as mitotane.
The term “immunotherapy agents” refers to those agents which use the own immune system to fight cancer. Immunotherapy can boost or change how the immune system works so it can find and attack cancer cells. Non-limiting examples of immunotherapy agents include immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab; interferons, interleukins, oncolytic viruses, chimeric antigen receptor T cell (CAR-T) products or cytokines. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the chemotherapy agents are selected from the group consisting of antimetabolites, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antitumor antibiotics, protein kinase inhibitors, enzymes, proteasome inhibitors, PARP inhibitors, histone deacetylase inhibitors.
In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the drug combination of the invention comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, in particular asenapine or a salt thereof, and b) one or more anticancer agents selected from the group consisting of methotrexate, pemetrexed, cytarabine, 5-fluorouracil (5-FU), capecitabine, gemcitabine, 6-mercaptopurine (6-MP), azathioprine, fludarabine, cladribine, hydroxyurea, cyclophosphamide, ifosfamide, chlorambucil, melphalan, temozolomide, carmustine, lomustine, streptozocin, busulfan,
procarbazine, cisplatin, carboplatin, oxaliplatin, irinotecan, topotecan, etoposide, teniposide, vincristine, vinblastine, vinorelbine, docetaxel, and paclitaxel, eribulin, ixabepilone, epothilone, bleomycin, actinomycin D, doxorubicin, daunorubicin, idarubicin, mitomycin, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, afatinib, osimertinib, alectinib, crizotinib, dabrafenib, vemurafenib, encorafenib, trametinib, ibrutinib, ruxolitinib, palbociclib, L-asparaginase, bortezomib, carfilzomib, ixazomib, olaparib, vorinostat, romidepsin, anastrozole, exemestane, letrozole, tamoxifen, raloxifene, fulvestrant, toremifene, apalutamide, enzalutamide, darolutamide, bicalutamide, flutamide, and nilutamide, abiraterone, ketoconazole, goserelin, leuprolide, triptorelin, degarelix, medroxyprogesterone acetate, megestrol acetate, mitotane, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, interferons, interleukins, oncolytic viruses, chimeric antigen receptor T cell (CAR-T) products, and cytokines.
In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the drug combination is selected from the group consisting of: i) a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) cisplatin, ii) a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) carboplatin, iii) a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) gemcitabine.
As mentioned above, the drug combinations comprising a) a compound of formula (I), or a stereoisomer and/or a salt thereof, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents act synergistically against cancer as illustrated in the examples.
The term "synergy or synergistic” is used herein refers to the fact that the effect observed by the combination is greater than the sum of the effects (additive effect) obtained independently with each one of the components of the drug combination. The synergy can be determined e.g. by Compusyn software analysis of cell viability assays results.
Pharmaceutical compositions and kits of parts
The present invention also relates to pharmaceutical compositions comprising the compounds of formula (I), or stereoisomers and/or a salt thereof as previously defined, as well as to pharmaceutical compositions and kits of parts comprising the drug combinations defined herein.
Accordingly, the invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a stereoisomer and/or a
salt thereof, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the compound of formula (I) or a salt and/or a stereoisomer thereof is the only active ingredient of the composition.
The invention also relates to a single pharmaceutical composition which comprises: a) a therapeutically effective amount of a compound of formula (I), or a salt and/or a stereoisomer thereof; b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents; and one or more pharmaceutically acceptable excipients or carriers.
The term "single pharmaceutical composition" as used herein refers to a dosage form that contains both a) and b) in the same composition.
The present invention also relates to a kit of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound of formula (I), or a salt and/or a stereoisomer thereof, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions.
For the purposes of the invention, the term “kit-of-parts or package” refers to a combined preparation, wherein the active ingredients a) and b) are physically separated and form part of different compositions although these compositions are packaged or marked for use together. In the context of the present invention “for use together or in combination" does not limit the order in which the therapeutic agents are administered. Thus, the compound of formula (I) or a salt and/or a stereoisomer thereof may be administered prior to, concomitantly with, or subsequent to the administration of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
The expression "therapeutically effective amount" as used herein, refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The specific dose of the compound to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration.
The expression "pharmaceutically acceptable excipients or carriers" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
Suitable pharmaceutical compositions to be used in the present invention are well-known in the art. The election of the pharmaceutical formulation will be determined by the skilled person depending upon the nature of the active compounds present in the composition, and its route of administration. Any route of administration may be used, for example oral, parenteral and topical administration.
The pharmaceutical composition may be formulated for oral administration and may contain one or more physiologically compatible carriers or excipients, in solid or liquid form. For example, formulations suitable for oral administration may include liquid solutions, suspensions, capsules, sachets or tablets, emulsions or dry powdered forms suitable for reconstitution with water.
The pharmaceutical composition may also be formulated for parenteral administration in combination with conventional injectable liquid carriers, such as water or suitable alcohols. Conventional pharmaceutical excipients for injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions. These pharmaceutical compositions may be injected intramuscularly, intraperitoneally, or intravenously.
The pharmaceutical composition may also be formulated for topical administration. Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. Uses
The compounds of formula (I) and stereoisomers and/or salts thereof, as well as the drug combinations disclosed herein, are useful in the treatment and/prevention of cancer.
The terms "treat, treatment or treating" refer to having a therapeutic effect, in particular to ameliorating symptoms associated with a disease or disorder, including delaying the onset of the disease or disorder symptoms, and/or lessening the severity or frequency of symptoms of the disease or disorder. Treating includes inhibition of tumor growth, maintenance of inhibited tumor growth, induction of remission, and metastasis of a tumor. The term "prevent, prevention or preventing" refers to decreasing the probability that an organism contracts or develops an abnormal condition.
The terms “cancer and tumor” as used herein interchangeably to refer to the pathological condition in mammals, including humans, that is typically characterized by unregulated cell growth. While these terms may include both benign or malignant growths, it is of particular interest of this invention the treatment and/or prevention of malignant tumors and cancers which are often resistant to treatment, may spread to other parts of the body and may be recurrent after they have been removed. The term “primary cancer” refers to the original, or first, cancer in the body. Cancer cells from a primary cancer may spread to other parts of the body and form new, or secondary, cancers. The term “metastatic cancer” refers to a cancer which arises in one organ and only later spreads to other organs.
Thus, the invention relates to a compound of formula (I) or a stereoisomer and/or salt thereof, for use in the treatment and/or prevention of cancer. This aspect may also be formulated as a method of treatment and/or prevention of cancer, which comprises administering to a subject in need thereof, including a human, a therapeutically effective amount of a compound of formula (I) or a stereoisomer and/or salt thereof, together with one or more pharmaceutically acceptable excipients or carriers. It also forms part of the invention the use of a compound of formula (I) or a stereoisomer and/or salt thereof, for the manufacture of a medicament for the treatment and/or prevention of cancer.
Further, the invention also relates to a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I), or a stereoisomer and/or salt thereof, for use in the treatment and/or prevention of cancer.
It also forms part of the invention the drug combination, the single pharmaceutical composition, or the kit of parts as previously defined, for use in the treatment and/or prevention of cancer. This aspect may also be formulated as a method of treatment and/or prevention of cancer, which comprises administering to a subject in need thereof, including a human, a therapeutically effective amount of the combination comprising a) a compound of formula (I) or a stereoisomer and/or salt thereof, b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents; and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the method of treatment and/or prevention of cancer comprises administering to a subject in need thereof, including a human, a single pharmaceutical composition as defined herein, or alternatively, a kit of parts as defined herein.
It also forms part of the invention the use of a drug combination comprising: a) a compound of formula (I) or a stereoisomer and/or salt thereof, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents, for the manufacture of a medicament for the treatment and/or prevention of cancer. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the medicament comprises a single pharmaceutical composition as defined herein, or alternatively, a kit of parts as defined herein.
According to one particular embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the treatment and/or prevention of cancer comprises the simultaneous, concurrent, separate or sequential administration of the compound of formula (I) or a stereoisomer and/or salt thereof, and one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
The present invention also relates to a compound of formula (I), or a stereoisomer and/or salt thereof, for use in combination therapy in the treatment and/or prevention of cancer,
wherein the compound of formula (I), or a stereoisomer and/or salt thereof, is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein.
Further, the invention also relates to one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined herein for use in combination therapy in the treatment and/or prevention of cancer, wherein the one or more anticancer agents are to be administered simultaneously, concurrently, separately or sequentially with a compound of formula (I), or a salt and/or a stereoisomer thereof.
The term "simultaneously" as used herein means administering the compound of formula (I) and the anticancer agent or agents at or about the same time. The term “concurrently” as used herein means that a dose of a first drug (either the compound of formula (I) or the anticancer agent or agents) is administered prior to the end of the dosing interval of the second drug. The term "separately" means administering the compound of formula (I) on the one hand, and the anticancer agent or agents on the other hand, at different times.
The term "sequentially" means administering in a specific order, where one first drug (either the compound of formula (I) or the anticancer agent or agents) is administered first, and then, the second one is administered after an interval of predetermined time.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the treatment and/or prevention of cancer is mediated by the inhibition of survivin (FIG. 4).
For the purposes of the invention, the term “inhibition of survivin” as used herein refers to the fact that the compounds of formula (I) or salts and/or stereoisomers thereof, particularly asenapine, are able to block, partially block, interfere, decrease, suppress, reduce or deactivate survivin.
The expression “treatment and/or prevention of cancer mediated by the inhibition of survivin” as used herein refers to the treatment of cancer which is characterized by an inhibition or downregulation of survivin.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the cancer is selected from the group consisting of hematological tumors, and solid tumors.
In one embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, wherein the cancer is other than breast cancer, more particularly the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
Thanks to its ability to cross the blood-brain barrier (BBB), asenapine may be of special interest in the treatment of brain tumors, including primary brain tumors or cancers with brain metastases.
In another embodiment, optionally in combination with one or more features of the various embodiments described above or below throughout all the description, the cancer is selected from the group consisting of lung cancer, more particularly lung adenocarcinoma; colorectal cancer, more particularly colon adenocarcinoma; neuroblastoma, more particularlypediatric neuroblastoma; sarcoma, more particularly pediatric sarcoma, and glioblastoma.
Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.
Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
Examples
Compounds Asenapine (MedChem Express, 1032481579) or Asenapine Maleate (AM)
(MedChemExpress, HY-11100) were dissolved in dimethyl sulfoxide (DMSO, Sigma- Aldrich, St. Louis, USA). Subsequent solutions for biological assays were made in media for in vitro experiments or PBS with 7.5% DMSO and 0.8% Tween20, for in vivo experiments. The chemotherapeutics used for the combination assays were cisplatin (Accord, Barcelona, Spain), carboplatin (TCI, Tokio, Japan), and gemcitabine (SUN pharma, Goregaon, Mumbai). 1-acetyl-N-(5-chloro-3-(4-(2-chloro-5- (trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N- methylpiperidine-4-carboxamide (compound Abbot 23b as described in Wendt et al., Bioorg. Med. Chem. Lett. 2007, 17, 3122-3129).
Cell line and culture conditions
A549 (human epithelial adenocarcinoma), SW620 (human colon carcinoma), HFL-1 (normal human lung fibroblast), U87 (human glioblastoma), LAN-1 (human neuroblastoma bone marrow metastasis) RD (pediatric rhabdomyosarcoma) and LLC1 (mouse Lewis lung carcinoma) commercial cell lines were obtained from the American Type
Culture Collection (ATCC, Manassas, VA, USA). LLC1, A549, SW620 and U87 cell lines were maintained in DMEM (Biological Industries, Beit Haemek, Israel) supplemented with 100 U/mL penicillin, 100 pg/mL streptomycin and 2 mM L-glutamine, all from Biological Industries, and 10% fetal bovine serum (FBS; Gibco, Paisley, UK). HFL-1 cells were maintained in F12[HAM] Nutrient Mixture (Biological Industries) supplemented with the already mentioned factors (100 U/mL penicillin, 100 ug/mL streptomycin and 2 mM L- glutamine and 10% FBS). LAN-1 and RD cell lines were cultured in Roswell Park Memorial Institute medium (RPMI, Biological industries) with 100 U/mL penicillin, 100 ug/mL streptomycin and 2 mM L-glutamine and 10% FBS. They all were maintained in a 5% CO2 incubator.
Viability Assays
Dose-response curves of AM, the chemotherapeutics and its combination were developed in order to calculate the inhibitory concentrations (IC) of 25%, 50% and 75% of cell population. To do so, cells (105 cells/well) were seeded in 96-well microtiter plates and were incubated for 24 h to allow cells to attach. Afterwards, they were treated for 24 h with the compounds. The concentrations tested were 0.0003-0.04 mg/mL for AM, 0.001- 0.1 mg/mL for cisplatin, 0.008-1 mg/mL for carboplatin, and 0.031-4 mg/mL for
gemcitabine. The chemotherapeutics and AM were used for the combination experiments, in which 105 cells/well were seeded in 96-well microtiter plates. 24 h later, cells were treated with AM, cisplatin /carboplatin /gemcitabine (at the same concentration ranges than before) or AM (0.015 mg/ml_) + cisplatin /carboplatin /gemcitabine.
In all experiments, after 24 h of treatment, 10 mM of 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide diluted in 1x PBS (MTT, Sigma-Aldrich) was added to each well for an additional 2 h. The medium was removed and the MTT formazan precipitate was dissolved in 100 pl_ of DMSO. Absorbance was read on a Multiskan multiwell plate reader (Thermo Fisher Scientific Inc., Waltham, MA, USA) at 570 nm. For each condition, at least three independent experiments were performed in duplicate. Cell viability was expressed as a percentage of control cells, and data are shown as the mean value ± S.D. The IC25, IC50 and IC75 values were calculated with GraphPad Prism™ 5 software (Graph Pad Software, San Diego, CA, USA).
Surface Plasmon Resonance assay ( SPR )
SPR assays were designed to monitor the interaction between ligand Survivin (Calmodulin tag; Abcam87202) and the tested compounds. Survivin ligand was immobilized following Biacore T200 protocol in a sensor chip CM5 (GE Healthcare BioSciences AB). This is coated with a carboxymethylated dextran matrix that allows a covalent protein attachment by amine coupling. In addition, since survivin ligand is tagged with calmodulin, calmodulin (Abcam78694) ligand alone was also immobilized in a channel that would be used as a reference channel. Prior to immobilization, in order to determine the optimal pH to pre-concentrate the ligand over the matrix, a pH scouting was performed. The ligand was diluted to 1 mM in 10 mM acetate buffers with pH 4 and 4.25, and injected during 180 s with a flow of 5 pL/min over an unmodified sensor chip. Then, the surface was regenerated with 50 mM NaOH to ensure no ligand remains bound to the surface. Once the optimum pH was selected, the surface of the sensor chip was activated with a mixture 1:1 of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDO) and N- hydroxysuccinimide (NHS) in order to form reactive ester groups on the surface.
Subsequently, Survivin protein was diluted to 0.05 pg/pL in 10 mM acetate buffer with pH 4.25 and immobilized in flow-cell 2 up to 1600 RU. Similarly, calmodulin protein was diluted to 0.05 pg/pL in 10 mM acetate buffer with pH 4 and immobilized in flow-cell 1 up to 1300 RU. The immobilized ligand level was previously calculated according to the relative molecular weights of the ligand and the analyte and the maximum binding capacity of the surface with a theoretical Rmax (maximal response) of 50 RU. Once the immobilization was performed, ethanolamine solution was injected in order to deactivate the remaining reactive groups of the surface.
Test compounds were stored as stock solution in 100% DMSO at -20 °C. The compounds were diluted with running buffer, 1 x HBS-P (HEPES-buffered saline 0.005% P20) 5% DMSO, at concentrations ranging from 0.012 mM to 40 mM. Afterwards, samples were injected in duplicates in both channels at 30 pL/min flow for 90 s and a dissociation time of 300 s. Moreover, a solvent correction with carefully prepared DMSO reference solutions ranging from 4.5% to 5.8% was run. Solvent correction was performed to adjust measured sample responses due to solvent effects on the bulk refractive index variations. Experiments were performed with the instrument temperature (flow cell, sensor chip, and sample compartment temperature) set to 25 °C. For affinity evaluation, Biacore T200 evaluation software 2.0 was used for subtraction of reference and blank data, along with solvent correction as well as for curve fitting, using the 1:1 Langmuir model.
Immunoblot analysis Culture medium was collected, and cells were washed with 1 X PBS twice. Both collected medium and 1 X PBS from washes were mixed and centrifuged at 300 g for 5 min to pellet death cells. Afterwards, supernatant was discarded, and the cell death pellet was preserved at 4 °C. Whole cell lysate (WCL) from cultured cells was prepared with ice cold lysis buffer containing 0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate, 50 mmol/L sodium fluoride, 40 mmol/L b-glycerophosphate, 200 pmol/L sodium orthovanadate, 1 mmol/L phenylmethylsulfonyl fluoride (all from Sigma-Aldrich), and protease inhibitor cocktail (Roche Diagnostics) in 1X PBS followed by its homogenization using a scrapper. WCL was collected and mixed thoroughly by vortexing with preserved cell death pellet at 4 °C. Subsequently, WCL was sonicated to degrade DNA followed by centrifugation at 16000 g during 15 min at 4 °C. Supernatant was collected in a final tube and the pellet was discarded. Protein concentration was determined by BCA protein assay (Pierce™, Thermo Fisher Scientific Inc.) following manufacturer’s instructions and using BSA protein (Sigma-Aldrich) to create a standard curve that was taken as reference to calculate the protein concentration in our samples, based on their absorbance. This procedure was performed in 96 well plates in duplicate and absorbance was read by using a multi-well plate reader (Multiskan FC, Thermo Fisher Scientific Inc.) at 562 nm.
Laemmli buffer containing Tris-HCI 250 mM pH 6.8, 10% SDS, 50% Glycerol, 0.01% Bromophenol Blue 25% 2-mercaptoethanol was added to the samples and these were boiled at 95 °C for 5 min. After that, 40 pg of protein extracts were loaded in 15% SDS- polyacrylamide gel electrophoresis. The gels were run at 80 V for 20 min followed by a voltage change to 120 V for approximately 90 min in Running Buffer (25 mM Tris, 192 mM Glycine, 0.1% SDS) and transferred to PVDF membrane as described above. Membranes
were incubated with primary antibodies (Table 1), according to the manufacturer's instructions.
Antibody Dilution Produced in Brand Catalog number
Anti-GAPDH 1 :500 Mouse Santa Cruz Biotechnology Inc. sc-47724
Anti-Survivin 1 :1000 Rabbit Cell Signaling Technology Inc. 2808
Anti-XIAP 1 :1000 Rabbit Cell Signaling Technology Inc. 2045
Table 1. List of primary antibodies used for Western blot analysis.
The day after, the membranes were washed 3 times for 5 min each with TBS-Tween and then incubated with horseradish peroxidase (HRP) conjugated secondary antibodies diluted 1:5000 in blocking solution for 1 h at RT with shaking. The secondary antibodies used were: donkey anti-mouse IgG-HRP (Cat#A16017) and donkey anti-rabbit IgG-HRP (Cat#A16029), both from Thermo Fisher Scientific Inc. After 3 washes in TBS-Tween for 10 min each, images were captured on an Image Quant LAS 500 (GE Healthcare) using ECL™ Western blotting detection reagent (Cat#RPN2106, Amersham, GE Healthcare, Buckinghamshire, UK). Band densitometries were retrieved using the Image Studio Lite software (v5.2, LI-COR Biosciences). GAPDH was used as gel loading control. The results shown are representative of Western blot data analysis obtained from at least three independent experiments.
Animals
All animal studies were approved by the Autonomic Ethic Committee (Generalitat de Catalunya) under the protocol #10928. C57BL6/FVBN/B6SJL mice were donated by Tyler Jacks from the Massachusetts Institute of Technology (MIT, Cambridge, MA).
In AM toxicity assay, ten-week-old mice were separated in 4 different groups (4 mice/group): vehicle (7.5% DMSO and 0.8% Tween20 in PBS), 10 mg/kg, 15 mg/kg and 20 mg/kg AM treated. The treatment was intraperitoneally injected once a day in a 5-days- on/2-days-off schedule. Body weight was recorded daily until the end of the treatment. Once mice were sacrificed, blood, liver, kidneys, spleen and brain were extracted and weighted. Organs were fixed in 4% paraformaldehyde (PFA) at 4 °C for 24 h. Then, the samples were processed for hematoxylin and eosin (HE) staining and were analyzed on the microscope.
For AM efficacy assay and combination efficacy assay, a subcutaneous mice model was used and 100 pL of 5-104 LLC1 cells in PBS:Matrigel (Corning) (1:1) were inoculated into the mice right flank. When tumors reached around 40 mm3, tumor-bearing mice were separated into 2 groups and treated with vehicle or 10 mg/kg of AM once a day on a 5- days-on/2-days-off schedule for 22 days for the AM therapeutic assay. For the combination efficacy study, mice were treated with AM (5 mg/kg, 5 days per week),
cisplatin (3 mg/kg days 0, 3 and 6), AM plus CisPt in combination or vehicle. Body weight and tumor volume were daily recorded.
Tumor volume was calculated by following formula: width2 x length/2. Mice were sacrificed and tumors were extracted and weighted. Tumors were kept in PBS until all of them were collected and then they were photographed. Tumors were fixed in 4% PFA at 4°C. After 24 h, samples were processed for HE staining and were analyzed on the microscope.
Statistical and Data Mining Analysis
For statistical analysis of western blot and MTT assay data, one-way ANOVA with post hoc Tukey analysis was carried out using the Statgraphics plus 5.1 statistical Software. The in vivo results were analyzed with GraphPad Prism 8 using the nonparametric Mann- Whitney U test or Kruskal Wallis test. Statistically significant differences, p < 0.05, p <
0.01, p < 0.001 and p < 0.0001, are represented by *, **, ***, **** respectively. Effect of AM on cell viability of tumor and non-tumor cell lines
In order to evaluate the cytotoxic effect of asenapine on healthy and cancer cells, non tumor human lung fibroblasts HFL-1 and lung A549 and colon SW620 cancer cells were treated with asenapine. Results were obtained from at least three independent experiments and are shown in FIG. 1. As it can be seen, treatment with asenapine at 5 mM for 24 h resulted to be non-cytotoxic in HFL-1 , showing statistically differences with both treated cancer cells, which cell viability was reduced below 71%. Moreover, despite treatment with asenapine at 20 pM showed a moderate decrease of HFL-1 cell viability, this reduction was statistically less significant compared to A549 and SW620 cells, where cell viability decreased to 0.6 and 0.4%, respectively.
In order to evaluate the sensitivity of cancer cells to asenapine maleate (AM), A549 and SW620 cells were treated at different concentrations (in a range between 0.8 and 100 pM) for 24 h. Moreover, since AM can easily cross the blood-brain barrier, due its tetracyclic structural nature, it was also considered of interest evaluating the cytotoxic effect of AM on the glioblastoma cell line U87, for its possible application in the treatment of brain cancers and brain metastasis. Furthermore, pediatric neuroblastoma and sarcoma cells were also evaluated after AM treatment, since they are malignancies with limited successful treatments approved. Experiments were carried out in triplicates. Results are shown in FIG. 2.
Evaluation of binding to survivin protein through Surface Plasmon Resonance (SPR) technology
To further characterize AM potential binding with survivin, it was proposed to monitor the direct interaction between survivin and AM by SPR assays. This real-time interaction analysis represents a valuable methodology which allows kinetics and affinity evaluation as well as determination of binding specificity between proteins and small molecules. Binding assays were performed using the Biacore T200 system. First the recombinant protein survivin was immobilized on a sensor surface. Calmodulin was also immobilized on another sensor surface, and was used as a reference channel, since survivin ligand is tagged with calmodulin. Next, analytes AM and Abbott23b were injected in solution as well as in duplicates over the sensor surface at concentrations ranging from 0.012 to 40 mM. Abbott23b was used as a positive control due to its already described high capacity to interact with the dimer interface of survivin. Changes in SPR response were collected and analyzed using the Biacore T200 Evaluation Software, included in the system. These changes, expressed in response units (RU), showed the association and dissociation curves of the interactions among survivin and the analytes AM and Abbott23b (FIG. 3 A), allowing in turn to obtain the affinity curves (FIG. 3 B). The data collected showed a binding constant (KD) in the low micromolar range. From the affinity curve, a KD of 25.72 pM for AM was obtained, which was slightly superior to the KD obtained for Abbott23b that was 4.11 pM. It is important to mention that small molecules like AM have fewer potential sites for intermolecular binding than larger molecules; therefore, the values obtained may reflect a high affinity of AM to the ligand, suggesting that the small molecule forms a complex with survivin.
Evaluation of survivin inhibition specificity
After SPR analysis, the molecular mechanism of action of AM in vitro was evaluated to elucidate whether the inhibitory effect observed is specific for survivin protein compared to another protein that belongs to the same protein family, the inhibitory of apoptosis proteins (IAP) family. Thereby, A549 cells were treated with AM at the IC50 for 24 h in order to investigate a possible inhibitory effect on lAPs protein levels. Results were obtained from at least three independent experiments and are shown in FIG. 4. As can be observed, AM was able to significantly decrease survivin at protein level. By contrary, the survivin partner protein inhibiting apoptosis, XIAP, did not show significant differences between AM treated cells and non-treated cells. Therefore, AM is able to specifically inhibit survivin protein levels but not its closely related protein XIAP. In vivo toxicity AM evaluation
In order to evaluate AM toxicity in vivo and determine the maximum tolerated dose for the efficacy studies, 3 different doses of AM (10, 15, 20 mg/kg), or vehicle, were administered intraperitoneally to C57BL/6 mice inoculated with mouse Lewis lung carcinoma cell line
(LLC1), following a schedule of 5 consecutive days per week. Mice weight was monitored during treatment and represented as difference of weight (W), in percentage, respect to initial weight. Organs were weighed and represented as percentage of mice weight. Results are shown in FIG. 5 and FIG. 6, respectively. Although mice lost some weight the first 2 days of each cycle, they all recovered and did not show any differences compared to control mice weight at the end of the experiment (FIG. 5). However, mice showed slightly transient secondary effects, such as low motility after drug administration, compatible with sedation or somnolence typically induced by antipsychotic drugs.
On the other hand, vital organs did not present macroscopic differences comparing all groups. Neither the organ’s weights showed significant changes among groups, indicating that doses below 20 mg/kg, administered 5 days per week, are safe and can be used in efficacy studies (FIG. 6).
In vivo efficacy AM assay A subcutaneous tumor model, C57BL/6 mice inoculated with mouse Lewis lung carcinoma cell line (LLC1), was used to test the efficacy of AM at 10 mg/kg. AM was intraperitoneally administered at the same dose schedule as the toxicity assay (5 successive days per week) for a total of 3 weeks. Mice weight was monitored during treatment and represented as difference of weight (W), in percentage, respect to initial weight. Results are shown in FIG. 7. As can be observed, mice weight of treated mice was similar to that of control group. On the other hand, treated tumors with 10 mg/kg of AM grew slower than those on the control group (FIG. 8). These results suggest that AM may impair tumor growth at 10 mg/kg. Combination therapy evaluation of AM with conventional chemotherapeutics
Combination experiments with AM and the first-line chemotherapeutics used in lung cancer treatment, such as cisplatin (Cis), carboplatin (CbPt), and gemcitabine (Gem), were performed in A549 lung adenocarcinoma cells. As observed in FIG. 9 and FIG. 10, IC50 values and cell viability significantly decreased when combining AM with Cis, CbPt and Gem, showing a synergistic effect analyzed by Compusyn software.
In vivo combination therapy efficacy assay
A subcutaneous tumor model, C57BL/6 mice inoculated with mouse Lewis lung carcinoma cell line (LLC1), was used to test the efficacy of AM in combination with the chemotherapeutic agent cisplatin. AM and/or cisplatin were intraperitoneally administered at 5 mg/kg AM (5 days per week), 3 mg/kg cisplatin (Days 0, 3 and 6), AM plus CisPt in combination or vehicle (V). Mice weight was monitored during treatment and represented as difference of weight (W), in percentage, respect to initial weight. Tumor volume was
also monitored during the experiment and tumor weight was assessed at the end of the experiment. Results are shown in FIG. 11. Mice weight slightly decreased when treated with cisplatin or AM plus cisplatin, however, it was recovered at the end of the experiment (FIG 11 A). The combination treatment of AM plus cisplatin showed the highest decrease in tumor volume growth (FIG.11B) and in tumor weight (FIG.11C), compared with mice treated with AM or cisplatin alone, suggesting a sensitization to the chemotherapeutic agent cisplatin when administered in combination with AM.
CITATION LIST
Patent Literature
- US4145434
- WO2016062285
- EP3708161
Non-Patent Literature
- Zhang W. et al. , “Antiproliferative activities of the second-generation antipsychotic drug sertindole against breast cancers with a potential application for treatment of breast-to- brain metastases”, Sci Rep 2018 Oct 25;8(1): 15753 - Wendt M.D. et al., “Discovery of a novel small molecule binding site of human survivin’’,
Bioorg. Med. Chem. Lett. 2007, 17, 3122-3129
For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:
Clause 1. A compound of formula (I) as defined herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I) or of any of its salts, for use in the treatment and/or prevention of cancer.
Clause 2. The compound for use according to clause 1 , wherein the compound of formula (I) is in the form of a salt which is asenapine maleate.
Clause 3. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in any of clauses 1-2, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
Clause 4. The compound for use according to any of clauses 1-2, or the pharmaceutical composition for use according to clause 3, wherein the treatment and/or prevention of cancer is mediated by the inhibition of survivin.
Clause 5. The compound or composition for use according to any of clauses 1-4, wherein the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
Clause 6. The compound or composition for use according to any of clauses 1-5, wherein the cancer is other than breast cancer, more particularly the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
Clause 7. The compound or composition for use according to any of clauses 1-6, wherein the cancer is lung cancer, more particularly lung adenocarcinoma.
Clause 8. The compound or composition for use according to any of clauses 1-6, wherein the cancer is colorectal cancer, more particularly colon adenocarcinoma.
Clause 9. The compound or composition for use according to any of clauses 1-6, wherein the cancer is neuroblastoma, more particularly pediatric neuroblastoma.
Clause 10. The compound or composition for use according to any of clauses 1-6, wherein the cancer is sarcoma, more particularly pediatric sarcoma.
Clause 11. The compound or composition for use according to any of clauses 1-6, wherein the cancer is glioblastoma.
Clause 12. A drug combination comprising: a) compound as defined in any of clauses 1-2, and
b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents and hormone therapy agents, more particularly the anticancer agents are chemotherapy agents.
Clause 13. The drug combination according to clause 12, which comprises a) compound as defined in any of clauses 1-2, and b) one anticancer agent selected from the group consisting of chemotherapy agents, immunotherapy agents and hormone therapy agents.
Clause 14. The drug combination according to clause 12, which comprises a) compound as defined in any of clauses 1-2, and b) two anticancer agents, which may belong to the same or to a different class, selected from the group consisting of chemotherapy agents, immunotherapy agents and hormone therapy agents.
Clause 15. The drug combination according to clause 13, wherein the anticancer agent is a chemotherapy agent.
Clause 16. The drug combination according to clause 15, wherein the chemotherapy agent is an antimetabolite, more particularly wherein the antimetabolite is selected from the group consisting of antifolates, pyrimidine antagonists, purine antagonists, and ribonucleotide reductase inhibitors; even more particularly wherein the antimetabolite is selected from the group consisting of methotrexate, pemetrexed, cytarabine, 5-fluorouracil (5-FU), capecitabine, gemcitabine, 6-mercaptopurine (6-MP), azathioprine, fludarabine, cladribine, and hydroxyurea.
Clause 17. The drug combination according to clause 15, wherein the chemotherapy agent is an alkylating agent, more particularly wherein the alkylating agent is selected from the group consisting of an oxazaphosphorine, nitrogen mustard, an imidazotetrazine, a nitrosourea, an alkyl sulfonate, a hydrazine, and a platinum-based agent; even more particularly wherein the alkylating agent is selected from the group consisting of cyclophosphamide, ifosfamide, chlorambucil, melphalan, temozolomide, carmustine, lomustine, streptozocin, busulfan, procarbazine, cisplatin, carboplatin, and oxaliplatin.
Clause 18. The drug combination according to clause 15, wherein the chemotherapy agent is a topoisomerase inhibitor, more particularly wherein the topoisomerase inhibitor is selected from the group consisting of a topoisomerase I inhibitor, and a topoisomerase II inhibitor; even more particularly wherein the topoisomerase inhibitor is selected from the group consisting of irinotecan, topotecan, etoposide, and teniposide.
Clause 19. The drug combination according to clause 15, wherein the chemotherapy agent is a mitotic inhibitor, more particularly wherein the mitotic inhibitor is selected from the group consisting of a vinca alkaloid, a taxane, and a nontaxane microtubule inhibitor; even more particularly wherein the mitotic inhibitor is selected from the group consisting of vincristine, vinblastine, vinorelbine, docetaxel, paclitaxel, eribulin, ixabepilone, and epothilone.
Clause 20. The drug combination according to clause 15, wherein the chemotherapy agent is an antitumor antibiotic, more particularly wherein the antitumor antibiotic is selected from the group consisting of bleomycin, actinomycin D, doxorubicin, daunorubicin, idarubicin, and mitomycin.
Clause 21. The drug combination according to clause 15, wherein the chemotherapy agent is a protein kinase inhibitor, more particularly wherein the protein kinase inhibitor is selected from the group consisting of a BCR-ABL tyrosine kinase inhibitor, a c-KIT tyrosine kinase inhibitor, an EGFR tyrosine kinase inhibitor, an ALK tyrosine kinase inhibitor, a V600E mutated-BRAF oncogene inhibitor, a MEK inhibitor, a Bruton tyrosine kinase inhibitor, a Janus kinase inhibitor, and a CDK inhibitor; even more particularly wherein the protein kinase inhibitor is selected from the group consisting of imatinib, dasatinib, nilotinib, erlotinib, gefitinib, afatinib, Osimertinib, alectinib, crizotinib, dabrafenib, vemurafenib, encorafenib, trametinib, ibrutinib, ruxolitinib, and palbociclib.
Clause 22. The drug combination according to clause 15, wherein the chemotherapy agent is an enzyme, more particularly L-asparaginase.
Clause 23. The drug combination according to clause 15, wherein the chemotherapy agent is a proteasome inhibitor, more particularly wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib.
Clause 24. The drug combination according to clause 15, wherein the chemotherapy agent is a PARP inhibitor, more particularly wherein the PARP inhibitor is olaparib.
Clause 25. The drug combination according to clause 15, wherein the chemotherapy agent is a histone deacetylase inhibitor, more particularly wherein the histone deacetylase inhibitor is selected from the group consisting of vorinostat and romidepsin.
Clause 26. The drug combination according to clause 13, wherein the anticancer agent is an immunotherapy agent.
Clause 27. The drug combination according to clause 26, wherein the immunotherapy agent is an immune checkpoint inhibitor, more particularly wherein the immune checkpoint inhibitor is selected from the group consisting of ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab.
Clause 28. The drug combination according to clause 26, wherein the immunotherapy agent is selected from the group consisting of an interferon, an interleukin, an oncolytic virus, a cytokine, and a chimeric antigen receptor T cell (CAR-T) product.
Clause 29. The drug combination according to clause 13, wherein the anticancer agent is a hormone therapy agent.
Clause 30. The drug combination according to clause 29, wherein the hormone therapy agent is an aromatase inhibitor, more particularly wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole.
Clause 31. The drug combination according to clause 29, wherein the hormone therapy agent is a selective estrogen receptor modulator, more particularly wherein the selective estrogen receptor modulator is tamoxifen or raloxifene.
Clause 32. The drug combination according to clause 29, wherein the hormone therapy agent is an estrogen receptor antagonist, more particularly wherein the estrogen receptor antagonist is fulvestrant or toremifene.
Clause 33. The drug combination according to clause 29, wherein the hormone therapy agent is an anti-androgen, more particularly wherein the anti-androgen is selected from the group consisting of apalutamide, enzalutamide, darolutamide, bicalutamide, flutamide, and nilutamide.
Clause 34. The drug combination according to clause 29, wherein the hormone therapy agent is a CYP17 inhibitor, more particularly wherein the CYP17 inhibitor is abiraterone or ketoconazole. Clause 35. The drug combination according to clause 29, wherein the hormone therapy agent is a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, more particularly wherein the luteinizing hormone-releasing hormone (LHRH) agonist or antagonist is selected from the group consisting of goserelin, leuprolide, triptorelin, and
degarelix.
Clause 36. The drug combination according to clause 29, wherein the hormone therapy agent is a progestin, more particularly wherein the progestin is medroxyprogesterone acetate or megestrol acetate.
Clause 37. The drug combination according to clause 29, wherein the hormone therapy agent is an adrenolytic, more particularly wherein the adrenolytic is mitotane. Clause 38. The drug combination according to clause 12, which comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) cisplatin.
Clause 39. The drug combination according to clause 12, which comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) carboplatin.
Clause 40. The drug combination according to clause 12, which comprises a) compound of formula (I) or a stereoisomer and/or a salt thereof, and b) gemcitabine.
Clause 41. A single pharmaceutical composition which comprises: a) a therapeutically effective amount of a compound as defined in any of clauses 1-2; and b) a therapeutically effective amount of one or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy agents as defined in any of clauses 15-37; and one or more pharmaceutically acceptable excipients or carriers.
Clause 42. A kit of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound in any of clauses 1-2, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy agents as defined in any of clauses 15-37, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions.
Clause 43. A drug combination as defined in any of clauses 12-40, a single pharmaceutical composition as defined in clause 41, or a kit of parts as defined in clause 42, for use in the treatment and/or prevention of cancer.
Clause 44. The drug combination for use according to clause 43, wherein the treatment and/or prevention of cancer is mediated by the inhibition of survivin. Clause 45. The drug combination for use according to any of clauses 43-44, wherein the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
Clause 46. The drug combination for use according to any of clauses 43-45, wherein the cancer is other than breast cancer, more particularly the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
Clause 47. The drug combination for use according to any of clauses 43-46, wherein the cancer is lung cancer, more particularly lung adenocarcinoma.
Clause 48. The drug combination for use according to any of clauses 43-46, wherein the cancer is colorectal cancer, more particularly colon adenocarcinoma. Clause 49. The drug combination for use according to any of clauses 43-46, wherein the cancer is neuroblastoma, more particularly pediatric neuroblastoma.
Clause 50. The drug combination for use according to any of clauses 43-46, wherein the cancer is sarcoma, , more particularly pediatric sarcoma.
Clause 51. The drug combination for use according to any of clauses 43-46, wherein the cancer is glioblastoma.
Clause 52. A compound as defined in any of clauses 1-2, for use in combination therapy in the treatment and/or prevention of cancer, wherein the compound is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy
agents as defined in any of clauses 15-37; more particularly wherein the cancer is as defined in any of the clauses 44-51.
Clause 53. One or more anticancer agents selected from chemotherapy agents, immunotherapy agents or hormone therapy agents as defined in any of clauses 15-37 for use in combination therapy in the treatment and/or prevention of cancer, wherein the one or more anticancer agents are to be administered simultaneously, concurrently, separately or sequentially with a compound as defined in any of clauses 1-2; more particularly wherein the cancer is as defined in any of the clauses 44-51.
Claims
2. The compound for use according to claim 1 , wherein the compound of formula (I) is in the form of a salt which is asenapine maleate.
3. A pharmaceutical composition which comprises a therapeutically effective amount of a compound as defined in any of claims 1-2, together with one or more pharmaceutically acceptable excipients or carriers, for use in the treatment and/or prevention of cancer.
4. The compound for use according to any of claims 1-2, or the pharmaceutical composition for use according to claim 3, wherein the treatment and/or prevention of cancer is mediated by the inhibition of survivin.
5. The compound for use according to any of claims 1-2, or the pharmaceutical composition for use according to claim 3, wherein the cancer is selected from the group consisting of lymphoma, pancreatic cancer, stomach cancer, liver cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, colon cancer, mesothelioma, urothelial cancer, esophageal cancer, melanoma, myeloma, prostate cancer, renal cancer, lung cancer, sarcoma, brain cancer, neuroblastoma, glioblastoma, and leukemia.
6. The compound or the pharmaceutical composition for use according to claim 5, wherein the cancer is selected from the group consisting of lung adenocarcinoma, colon
adenocarcinoma, pediatric neuroblastoma, pediatric sarcoma, and glioblastoma.
7. A drug combination comprising: a) compound as defined in any of claims 1-2, and b) one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents.
8. The drug combination according to claim 7, wherein the chemotherapy agents are selected from the group consisting of antimetabolites, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antitumor antibiotics, protein kinase inhibitors, enzymes, proteasome inhibitors, PARP inhibitors, and histone deacetylase inhibitors.
9. The drug combination according to claim 7, wherein the anticancer agents are selected from the group consisting of methotrexate, pemetrexed, cytarabine, 5-fluorouracil (5-FU), capecitabine, gemcitabine, 6-mercaptopurine (6-MP), azathioprine, fludarabine, cladribine, hydroxyurea, cyclophosphamide, ifosfamide, chlorambucil, melphalan, temozolomide, carmustine, lomustine, streptozocin, busulfan, procarbazine, cisplatin, carboplatin, oxaliplatin, irinotecan, topotecan, etoposide, teniposide, vincristine, vinblastine, vinorelbine, docetaxel, and paclitaxel, eribulin, ixabepilone, epothilone, bleomycin, actinomycin D, doxorubicin, daunorubicin, idarubicin, mitomycin, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, afatinib, osimertinib, alectinib, crizotinib, dabrafenib, vemurafenib, encorafenib, trametinib, ibrutinib, ruxolitinib, palbociclib, L-asparaginase, bortezomib, carfilzomib, ixazomib, olaparib, vorinostat, romidepsin, anastrozole, exemestane, letrozole, tamoxifen, raloxifene, fulvestrant, toremifene, apalutamide, enzalutamide, darolutamide, bicalutamide, flutamide, and nilutamide, abiraterone, ketoconazole, goserelin, leuprolide, triptorelin, degarelix, medroxyprogesterone acetate, megestrol acetate, mitotane, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, interferons, interleukins, oncolytic viruses, chimeric antigen receptor T cell (CAR-T) products, and cytokines.
10. The drug combination according to any of claims 7-9, which is selected from the group consisting of: i) a) compound as defined in any of claims 1-2, and b) cisplatin, ii) a) compound as defined in any of claims 1-2, and b) carboplatin, and iii) a) compound as defined in any of claims 1-2, and b) gemcitabine.
11. A single pharmaceutical composition which comprises: a) a therapeutically effective amount of a compound as defined in any of claims 1-2; and
b) a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and or hormone therapy agents as defined in any of claims 7-9; and one or more pharmaceutically acceptable excipients or carriers.
12. A kit of parts comprising: i) a first pharmaceutical composition which comprises a therapeutically effective amount of a) a compound in any of claims 1-2, together with one or more pharmaceutically acceptable excipients or carriers; and ii) a second pharmaceutical composition which comprises a therapeutically effective amount of one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined in any of claims 7-9, together with one or more pharmaceutically acceptable excipients or carriers; wherein compositions i) and ii) are separate compositions.
13. A drug combination as defined in any of claims 7-10, a single pharmaceutical composition as defined in claim 11, ora kit of parts as defined in claim 12, for use in the treatment and/or prevention of cancer.
14. A compound as defined in any of claims 1-2, for use in combination therapy in the treatment and/or prevention of cancer, wherein the compound is to be administered simultaneously, concurrently, separately or sequentially with one or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined in any of claims 7-9.
15. One or more anticancer agents selected from the group consisting of chemotherapy agents, immunotherapy agents, and hormone therapy agents as defined in any of claims 7-9 for use in combination therapy in the treatment and/or prevention of cancer, wherein the one or more anticancer agents are to be administered simultaneously, concurrently, separately or sequentially with a compound as defined in any of claims 1-2.
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