Methods of treating malignant peripheral nerve sheathing neoplasm (MPNST) using LSD1 inhibitors

Abstract

The present invention relates to LSD1 inhibitors for the treatment of malignant peripheral nerve sheathing neoplasm (MPNST). The invention also provides a method of treating MPNST in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor.

Description

[0001] field

[0002] The present invention relates to the field of therapy for malignant peripheral nerve sheath tumor (MPNST). In particular, the present invention provides LSD1 inhibitors for use in the treatment of MPNST. The present invention also provides a method of treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor.

[0003] background

[0004] Cancer is one of the leading causes of death worldwide. The clinical management of cancer has changed radically over the past few decades. In the past, cancer could only be treated with chemotherapy "dirty" drugs, which non-specifically restricted cell proliferation by interfering with DNA or basic cell cycle machinery. Today, new personalized and precision medicine approaches are designed to block the growth of cancer cells while primarily sparing other cells of the body. The advantage of this approach is that targeted therapies are less harmful to normal cells.

[0005] Epigenetics is one of the emerging fields of precision medicine for cancer, with the first generation of drugs approved by the FDA and more in clinical trials. Lysine-specific demethylase 1 (LSD1 or KDM1A) is an epigenetic enzyme that regulates gene expression by demethylating two different residues, lysine 4 (H3K4) and lysine 9 (H3K9), of the histone H3 tail with opposite effects. H3K4 demethylation is associated with transcriptional repression, while H3K9 demethylation is associated with transcriptional activation. In addition, LSD1 is a component of many multiprotein complexes that control enhancer-promoter contacts in gene repression, such as NurD and CoRest. LSD1 has been shown to play a key role in cancers such as leukemia and small cell lung cancer (SCLC), and is committed to the development of LSD1 inhibitors. Catalytic active site targeted inhibitors have been developed, such as iadademstat, bomedemstat, and pulrodemstat. These compounds bind deep within the active site of LSD1, blocking access to protein substrates (e.g., histone H3 tail) and non-substrate protein interactors (e.g., SNAG-domain transcription factors), thereby inhibiting the catalytic activity and scaffold interactions of LSD1. LSD1 inhibitors have been described as having potential antiproliferative activity in specific tumor types and are currently being tested in clinical trials as treatments for cancers such as acute myeloid leukemia (AML) and SCLC.

[0006] Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive tissue sarcoma. It may arise in at least three different contexts. Approximately 40-50% of MPNST cases occur in patients with neurofibromatosis type I, a dominant autosomal syndrome caused by mutations in the NF1 gene that predisposes patients to learning disabilities, musculoskeletal disorders, and a tendency to develop small benign tumors (neurofibromas). However, mutations in the NF1 gene are not sufficient to drive MPNST in patients with neurofibromatosis type I, and a series of further mutational events must accumulate, such as loss-of-function mutations in tumor suppressor genes other than NF1 (e.g., CDKN2A, p53, or PTEN) and / or mutations or copy number variations in oncogenes (e.g., EGFR or c-Met). In addition, in many cases, the activity of the polycomb repressive complex 2 (PRC2) is also lost, a multiprotein complex involved in processes such as methylation of histone H3 lysine 27 (H3K27), a known epigenetic post-translational modification that is often associated with transcriptional repression. About 40% of MPNST are sporadic and have no known genetic cause. The remaining about 10% occur due to prior radiotherapy. Typically, MPNST has an aggressive clinical course, a recurrence probability of 50%, and an overall average 5-year survival rate of only 20-40%. Advanced disease usually leads to lung and bone metastases. There is currently no drug specifically approved for the treatment of MPNST. Although a variety of different drugs have been tested in clinical trials of MPNST, these drugs have shown disappointing response rates, with almost no MPNST patients achieving disease stabilization at most (see, e.g., Martin E et al., Crit Rev Oncol Hematol, 2019, 138: 223-32, doi: 10.1016 / j.critrevonc.2019.04.007). Therefore, there is a huge unmet medical need for finding new and more effective MPNST treatment methods. The present invention addresses this need and other needs. SUMMARY OF THE INVENTION

[0008] The present invention is based on the surprising discovery that LSD1 inhibitors, such as adalastat, pomadestat and prolodrumostat, are advantageously effective in treating MPNST, as also described in Example 1 below. This was completely unexpected, especially as MPNST is a malignant tumor that is highly aggressive and extremely difficult to treat. Therefore, the present invention provides new and improved therapeutic methods for treating MPNST.

[0009] Therefore, the present invention relates to LSD1 inhibitors for use in the treatment of MPNST.

[0010] The present invention also relates to a pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients, which is used for treating MPNST.

[0011] The present invention also provides a method of treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor (or a therapeutically effective amount of a pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients).

[0012] In addition, the present invention relates to the use of LSD1 inhibitors in the treatment of MPNST.

[0013] The present invention also relates to the use of LSD1 inhibitors in preparing a drug (or a pharmaceutical composition) for treating MPNST. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 : Design of a 9×9 matrix analysis. From top to bottom, adrenaline was added in increasing concentrations at a 1:2 dilution, while from left to right, a combination of second active agents was added in increasing concentrations at a 1:2 dilution. The darker the grey, the higher the concentration of each active agent. The wells corresponding to the diagonal (horizontal) line of the plate represent fixed EC 50 ratio. Equivalent to the expected EC 50 The concentration of values ​​is centered horizontally and vertically on the plate for each active agent.

[0016] Figure 2 : Design of a 5×5 matrix analysis. From top to bottom, adrenaline was added in increasing concentrations at a 1:5 dilution, while from left to right, a combination of second active agents was added in increasing concentrations at a 1:5 dilution. The darker the grey, the higher the concentration of each active agent. The wells corresponding to the diagonal (horizontal) line of the plate represent fixed EC 50 ratio. Equivalent to the expected EC 50 The concentration of values ​​is centered horizontally and vertically on the plate for each active agent. DETAILED DESCRIPTION OF THE INVENTION

[0018] As explained above, the present invention is based on the surprising discovery that LSD1 inhibitors are advantageously effective in treating MPNST, as described in further detail below and in the Examples section. In particular, a broad panel of 12 different MPNST cell lines was tested in Example 1, which represents different subtypes of MPNST encountered in clinical practice, as it includes MPNST associated with neurofibromatosis type I and sporadic MPNST cell lines, and is characterized by significant genomic heterogeneity in terms of NF1 heterozygosity, ploidy, and mutation status of CDKN2A and PRC2. The exemplary LSD1 inhibitor adrenaline was found to be highly effective across the significant heterogeneity of MPNST cell lines and is therefore particularly suitable for treating MPNST. As also described in Example 1, other LSD1 inhibitors having different chemical backbones and including reversible and irreversible inhibitors of LSD1 have also been shown to be effective in treating MPNST.

[0019] Therefore, the present invention relates to LSD1 inhibitors for the treatment of MPNST. The present invention also relates to a pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients, the pharmaceutical composition being used to treat MPNST. The present invention also provides a method for treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor (or a therapeutically effective amount of a pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients). In addition, the present invention relates to the use of a LSD1 inhibitor in the treatment of MPNST. The present invention also relates to the use of a LSD1 inhibitor in the preparation of a medicament (or pharmaceutical composition) for the treatment of MPNST.

[0020] According to the present invention, "LSD1 inhibitor" refers to a compound that reduces, decreases, blocks or inhibits the gene expression, activity or function of LSD1. Examples thereof are provided below under the heading "LSD1 inhibitor". Preferred LSD1 inhibitors include each of adrenaline or a pharmaceutically acceptable salt thereof (e.g. adrenaline dihydrochloride), prodomostat or a pharmaceutically acceptable salt thereof (e.g. prodomostat besylate) and pomadestat or a pharmaceutically acceptable salt thereof (e.g. pomadestat bistosylate). A particularly preferred LSD1 inhibitor is adrenaline or a pharmaceutically acceptable salt thereof (e.g. adrenaline dihydrochloride).

[0021] Preferably, the LSD1 inhibitor (eg, adrenaline or a pharmaceutically acceptable salt thereof) is administered orally. Exemplary formulations that can be administered orally, particularly by oral ingestion, are described in more detail below.

[0022] The individual treated according to the present invention may be a human or an animal (eg, a non-human mammal), and is preferably a human.

[0023] The MPNST treated according to the present invention can be, for example, a neurofibromatosis type I-associated MPNST, a sporadic MPNST, or a radiation-induced MPNST.

[0024] As explained above, MPNST usually occurs in individuals with neurofibromatosis type I, which is a genetic disease. Therefore, in some embodiments, the MPNST treated according to the present invention is a MPNST associated with neurofibromatosis type I (or an MPNST associated with neurofibromatosis type I). Therefore, in some embodiments, the present invention relates to the treatment of MPNST in individuals with neurofibromatosis type I. The present invention also relates to an LSD1 inhibitor (or a pharmaceutical composition comprising a D1 inhibitor) for use in the treatment of MPNST, wherein the LSD1 inhibitor (or pharmaceutical composition) is administered to an individual with neurofibromatosis type I.

[0025] In some embodiments, the MPNST treated according to the present invention is a non-type I neurofibromatosis associated MPNST (or an MPNST unrelated to type I neurofibromatosis), in particular a sporadic MPNST or a radiation-induced MPNST. Therefore, the present invention particularly relates to treating MPNST in individuals who do not have type I neurofibromatosis. The present invention also relates to an LSD1 inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitor) for use in treating MPNST, wherein the LSD1 inhibitor (or pharmaceutical composition) is administered to an individual who does not have type I neurofibromatosis. In some embodiments, the MPNST treated is a sporadic MPNST. In some embodiments, the MPNST treated is a radiation-induced MPNST (see, e.g., Yamanaka R et al., World Neurosurg, 2017, 105: 961-970.e8, doi: 10.1016 / j.wneu.2017.06.010). The MPNST treated according to the present invention may also be an MPNST (including, for example, any of the above-mentioned special types of MPNST) having one or more mutations or genetic changes affecting the NF1 gene, in particular one or more inactivating mutations or inactivating genetic changes in the NF1 gene. Thus, the MPNST treated may be, for example, an MPNST associated with neurofibromatosis type I having one or more mutations or genetic changes (e.g., one or more inactivating mutations or inactivating genetic changes) in the NF1 gene, a sporadic MPNST having one or more mutations or genetic changes (e.g., one or more inactivating mutations or inactivating genetic changes) in the NF1 gene, or a radiation-induced MPNST having one or more mutations or genetic changes (e.g., one or more inactivating mutations or inactivating genetic changes) in the NF1 gene. Such inactivating mutations or inactivating genetic changes in the NF1 gene particularly include loss-of-function mutations and result in reduced or absent expression and / or stability and / or activity of its protein product, neurofibromin. In addition, such mutations or genetic changes may affect one or both alleles of the NF1 gene.

[0026] In humans, the NF1 gene is located on chromosome 17q11.2 and encodes a protein product called neurofibromin. The typical amino acid sequence length of human neurofibromin isoform 2 is 2839 residues (see, e.g., Uniprot identifier P21359-1; https: / / www.uniprot.org / uniprot / P21359.fasta), and the typical amino acid sequence length of isoform 1 is 2818 residues (see, e.g., Uniprot identifier P21359-2; https: / / www.uniprot.org / uniprot / P21359-2.fasta). These two isoforms are considered to be the most biologically relevant. Isoform 2 is present in most human tissues, but not in neurons of the central nervous system. The NF1 gene is able to produce other alternative splicing isoforms through different combinations of its approximately 60 exons. More than 3000 germline mutations in the NF1 gene have been reported in the Human Gene Mutation Database (HGMD; http: / / www.hgmd.cf.ac.uk / ac / index.php) and more than 1000 somatic mutations have been reported in The Cancer Genome Atlas (TCGA; https: / / www.cancer.gov / about-nci / organization / ccg / research / structural-genomics / tcga); see also Scheer M et al., Int J Mol Sci, 2021, 23(1): 352, doi: 10.3390 / ijms23010352. Many characterized mutations are loss-of-function, which means that they ultimately have a negative impact on the function of the protein product. At the gene level, all kinds of mutations have been described, including nonsense, missense, frameshift, gain-loss position (insertion or deletion), microdeletion, inversion, splice site variation, complete translocation and complex rearrangement. However, there is no clear local mutation aggregation pattern within the NF1 gene. To identify mutations or genetic alterations in the NF1 gene, it is recommended to apply a mutation detection pipeline to reliably characterize NF1 mutations, using a series of different algorithms that are specifically fine-tuned to detect single nucleotide variants (SNVs), gains and losses, or translocations in next-generation sequencing (NGS) reads. A sample, such as a biopsy sample obtained from an individual, can be evaluated for the presence of a mutation or genetic alteration in the NF1 gene.The domain structure of neurofibromin is complex and includes, from N-terminus to C-terminus: (1) N-thermal domain, which contains cysteine- and serine-rich domain / GTPase activation domain (CSRD) and tubulin binding domain (TBD); (2) GTPase-activation domain (GAP)-associated domain (GRD), which promotes the hydrolysis of active Ras-GTP to the inactive form of Ras-GDP; (3) Sec14 homology fragment; (4) pleckstrin homology (PH)-like domain; and (5) C-thermal domain, which contains thermal repeat domain (HLR) and C-terminal domain (CTD), in which the syndecan binding domain (SBD) is found. In addition, Sec14, PH-like and HLR domains constitute the components of the so-called leucine-rich domain (LRD). Dimerization sites are found scattered within the N-thermal domain (at the distal N-terminus and TBD) and particularly in the C-thermal domain. Typically, the MPNST treated according to the present invention may have one or more mutations or genetic alterations (particularly one or more inactivating mutations or inactivating genetic alterations) in the NF1 gene sequence of any one (or several) of the above-mentioned domains or fragments of the NF1 gene product neurofibromin. Thus, for example, the MPNST may be an MPNST having one or more inactivating mutations located in the GTPase activation domain (GAD)-related domain (GRD) of NF1. In some embodiments, the MPNST has one or more inactivating mutations in the cysteine- and serine-rich domain / GTPase activation domain (CSRD) of NF1. In some embodiments, the MPNST has one or more inactivating mutations located on at least one dimerization interface of NF1.

[0027] The MPNST treated according to the present invention may also be an MPNST without a mutation or genetic alteration affecting the NF1 gene, in particular an MPNST with a wild-type NF1 gene. Thus, the MPNST treated may be, for example, a sporadic MPNST with a wild-type NF1 gene or a radiation-induced MPNST with a wild-type NF1 gene.

[0028] In addition, the MPNST treated according to the present invention can be an MPNST (including, for example, any of the special types of MPNST mentioned above, such as neurofibromatosis type I-associated MPNST, sporadic MPNST or radiation-induced MPNST), which has one or more mutations or genetic changes that affect (especially reduce or inhibit) the expression and / or activity of CDKN2A, p53, RB1, PTEN and / or PRC2 (especially one or more inactivating mutations or inactivating genetic changes in the CDKN2A, p53, RB1, PTEN and / or PRC2 genes) and / or one or more mutations or genetic changes (also including, for example, copy number variations) that affect (especially activate or enhance) the expression and / or activity of EGFR, PDGFRA and / or c-Met (especially one or more activating mutations or activating genetic changes in the EGFR, PDGFRA and / or c-Met genes).

[0029] Thus, in particular, the MPNST to be treated may be an MPNST having one or more mutations or genetic changes that affect (in particular reduce or inhibit) CDKN2A expression and / or activity, in particular one or more inactivating mutations or inactivating genetic changes of CDKN2A (including, for example, any of the above-mentioned special types of MPNST, such as MPNST associated with neurofibromatosis type I, sporadic MPNST, or radiation-induced MPNST). Thus, the MPNST to be treated may be an MPNST associated with CDKN2A inactivation, including, for example, MPNST associated with neurofibromatosis type I associated with CDKN2A inactivation, sporadic MPNST associated with CDKN2A inactivation, or radiation-induced MPNST associated with CDKN2A inactivation. Such inactivation of CDKN2A (particularly bi-allelic inactivation of CDKN2A) can be attributed to, for example, one or more point mutations, inversions, deletions or translocations of CDKN2A (see, for example, Magallón-Lorenz M et al., Hum Genet, 2021, 140(8): 1241-52, doi: 10.1007 / s00439-021-02296-x).

[0030] The MPNST to be treated may also be an MPNST (including, for example, any of the above-mentioned special types of MPNST) having one or more mutations or genetic changes that affect (particularly reduce or inhibit) p53 expression and / or activity, particularly one or more inactivating mutations or inactivating genetic changes of p53. Thus, the MPNST to be treated may be an MPNST associated with p53 inactivation, including, for example, MPNST associated with neurofibromatosis type I associated with p53 inactivation, sporadic MPNST associated with p53 inactivation, or radiation-induced MPNST associated with p53 inactivation.

[0031] The MPNST to be treated may also be an MPNST (including, for example, any of the above-mentioned special types of MPNST) having one or more mutations or genetic changes that affect (particularly reduce or inhibit) RB1 expression and / or activity, particularly one or more inactivating mutations or inactivating genetic changes of RB1. Thus, the MPNST to be treated may be an MPNST associated with RB1 inactivation, including, for example, MPNST associated with neurofibromatosis type I associated with RB1 inactivation, sporadic MPNST associated with RB1 inactivation, or radiation-induced MPNST associated with RB1 inactivation.

[0032] The MPNST treated may also be an MPNST (including, for example, any of the above-mentioned special types of MPNST) with one or more mutations or genetic changes that affect (particularly reduce or inhibit) PTEN expression and / or activity, particularly one or more inactivating mutations or inactivating genetic changes of PTEN. Thus, the MPNST treated may be an MPNST associated with PTEN inactivation, including, for example, MPNST associated with neurofibromatosis type I associated with PTEN inactivation, sporadic MPNST associated with PTEN inactivation, or radiation-induced MPNST associated with PTEN inactivation.

[0033] The MPNST treated may also be an MPNST (including, for example, any of the above-mentioned special types of MPNST) having one or more mutations or genetic changes that affect (particularly reduce or inhibit) PRC2 expression and / or activity, particularly one or more inactivating mutations or inactivating genetic changes of PRC2. Thus, the MPNST treated may be an MPNST associated with PRC2 inactivation, including, for example, MPNST associated with neurofibromatosis type I associated with PRC2 inactivation, sporadic MPNST associated with PRC2 inactivation, or radiation-induced MPNST associated with PRC2 inactivation. Such inactivation of PRC2 may be due to, for example, one or more mutations in one or more PRC2 core component genes, such as EZH2, EED and / or SUZ12.

[0034] The MPNST treated may also be an MPNST (including, for example, any of the above-mentioned special types of MPNST) with one or more mutations or genetic changes that affect (particularly activate or enhance) EGFR expression and / or activity, particularly one or more activating mutations or activating genetic changes of EGFR. Thus, the MPNST treated may be an MPNST associated with EGFR activation or upregulation, including, for example, MPNST associated with neurofibromatosis type I associated with EGFR activation / upregulation, sporadic MPNST associated with EGFR activation / upregulation, or radiation-induced MPNST associated with EGFR activation / upregulation.

[0035] The MPNST treated may also be an MPNST having one or more mutations or genetic changes that affect (particularly activate or enhance) PDGFRA expression and / or activity, particularly one or more activating mutations or activating genetic changes of PDGFRA (including, for example, any of the above-mentioned special types of MPNST). Therefore, the MPNST treated may be an MPNST associated with PDGFRA activation or upregulation, including, for example, MPNST associated with neurofibromatosis type I associated with PDGFRA activation / upregulation, sporadic MPNST associated with PDGFRA activation / upregulation, or radiation-induced MPNST associated with PDGFRA activation / upregulation.

[0036] The MPNST to be treated may also be an MPNST having one or more mutations or genetic changes that affect (particularly activate or enhance) c-Met expression and / or activity, particularly one or more activating mutations or activating genetic changes of c-Met (including, for example, any of the above-mentioned special types of MPNST). Thus, the MPNST to be treated may be an MPNST associated with c-Met activation or upregulation, including, for example, MPNST associated with neurofibromatosis type I associated with c-Met activation / upregulation, sporadic MPNST associated with c-Met activation / upregulation, or radiation-induced MPNST associated with c-Met activation / upregulation.

[0037] The MPNST treated can also be an MPNST associated with chromosome 8 gain (including, for example, any of the special types of MPNST described above, such as MPNST associated with neurofibromatosis type I, sporadic MPNST, or radiation-induced MPNST) (see, for example, Dehner C et al., JCI Insight, 2021, 6(6):e146351, doi:10.1172 / jci.insight.146351).

[0038] The MPNST treated can also be an MPNST that overexpresses one or more SNAG-domain transcription factors, such as Snail1 (Snail), Snail2 (Slug), Snail3 (Smuc), Scratch 1, Scratch 2, Gfi-1, Gfi-1B, Insm1, Insm2, Ovol-1 (Ovo-like 1), Ovol-2 and / or Ovol-3 (including, for example, any of the above-mentioned special types of MPNST).

[0039] Furthermore, the MPNST treated can be an MPNST associated with aneuploidy (eg, where one or more chromosomes are present in more than two copies and / or an uneven copy number) (including, for example, any of the special types of MPNST described above).

[0040] The MPNST treated (including any of the above-mentioned special types of MPNST) may also be a metastatic MPNST. Thus, the MPNST treated may be a primary MPNST that has formed metastases, i.e., has spread to one or more other parts of the individual's body (e.g., lungs and / or bones). In particular, the MPNST may be, for example, a metastatic neurofibromatosis type I-associated MPNST, a metastatic sporadic MPNST, or a metastatic radiation-induced MPNST.

[0041] The MPNST treated (including any of the above-mentioned special types of MPNST) can also be a relapsed or refractory MPNST. In particular, the MPNST can be, for example, a relapsed or refractory MPNST associated with neurofibromatosis type I, a relapsed or refractory sporadic MPNST, or a relapsed or refractory radiation-induced MPNST.

[0042] The therapeutic effect of LSD1 inhibitors in treating MPNST can be further confirmed in additional in vitro or in vivo tests as well as clinical trials in humans, which can be easily established by those skilled in the art of drug development.

[0043] LSD1 inhibitors

[0044] As used herein, "LSD1 inhibitor" refers to a compound / substance that reduces, decreases, blocks or inhibits the gene expression, activity or function of LSD1. Compounds used as LSD1 inhibitors are known in the art. Generally, any molecule used as a LSD1 inhibitor can be used in the context of the present invention. Preferably, the LSD1 inhibitor is a small molecule. In addition, the LSD1 inhibitor can be an irreversible LSD1 inhibitor or a reversible LSD1 inhibitor. In addition, as shown in Example 1 below, according to the present invention, both irreversible and reversible LSD-1 inhibitors can be used to treat MPNST. Typical irreversible LSD1 inhibitors include cyclopropylamine-based compounds, such as adrenaline and pomadestat, which belong to the LSD1 inhibitors used in Example 1. A representative example of a reversible LSD1 inhibitor is the compound prolodrum depot, which is also used in Example 1. Preferably, the LSD1 inhibitor is a selective LSD1 inhibitor; as used herein, "selective LSD1 inhibitor" refers to a LSD1 inhibitor that exhibits at least a 10-fold (preferably at least a 100-fold) selectivity for LSD1 over other FAD-dependent monoamine oxidases, particularly MAO-A and MAO B (e.g., selectivity can be determined by measuring the IC values ​​of LSD1, MAO-A and MAO-B). 50 value to evaluate).

[0045] An exemplary list of small molecule LSD1 inhibitors is provided in the table below:

[0046]

[0047]

[0048] Thus, the LSD1 inhibitor used in the present invention may be, for example, any of the specific compounds listed in the above table or a pharmaceutically acceptable salt of any of these compounds.

[0049] In some embodiments, the LSD1 inhibitor is a LSD1 inhibitor known in the art, including, for example, any of the compounds disclosed in WO2010 / 043721, WO2010 / 084160, WO2010 / 143582, WO2011 / 035941, WO2011 / 042217, WO2011 / 131576, WO2011 / 131697, WO2012 / 013727, WO2012 / 013728, WO2012 / 045883, WO2012 / 135113, WO2013 / 022047, EP2743256A1, WO2 013 / 025805, WO2013 / 057320, WO2013 / 057322, WO2014 / 058071, EP2907802A1, WO2014 / 084298,EP2927212A1、WO2014 / 086790、WO2014 / 164867、WO2014 / 194280、WO2014 / 205213、WO2015 / 021128、WO2015 / 031564、WO2015 / 089192、WO2015 / 120281、WO2015 / 123408、WO2015 / 123424、WO2015 / 123437、WO2015 / 123465、WO2015 / 134973、WO2015 / 168466、WO2015 / 181380、WO2015 / 200843、WO2016 / 003917、WO2016 / 004105、WO2016 / 007722、WO2016 / 007727、WO2016 / 007731、WO2016 / 007736、WO2016 / 034946、WO2016 / 037005、WO2016 / 123387、WO2016 / 130952、WO2016 / 161282、WO2016 / 172496、WO2016 / 177656、WO2017 / 004519、WO2017 / 027678、WO2017 / 079476、WO2017 / 079670、WO2017 / 090756、EP3381896A1、WO2017 / 109061、WO2017 / 116558、WO2017 / 149463、WO2017 / 157322、EP3431471A1、WO2017 / 184934、WO2017 / 195216、WO2017 / 198780、WO2017 / 215464、EP3486244A1、WO2018 / 081342、WO2018 / 081343、WO2018 / 137644、EP3575285A1、WO2018 / 213211、WO2018 / 216800、EP3632897A1、WO2018 / 226053、WO2018 / 234978、WO2019 / 009412、WO2019 / 034774、WO2019 / 054766、WO2019 / 217972、WO2019 / 222069、WO2020 / 015745、EP3825309A1、WO2020 / 047198、WO2020 / 052647、WO2020 / 052649、EP3851440A1、WO2020 / 138398、WO2020 / 159285,EP3907225A1, WO2021 / 058024, WO2021 / 095835, WO2021 / 175079, WO2022 / 072811, WO2022 / 171044, WO2022 / 188709、WO2022 / 240886、WO2022 / 267495、WO2023 / 069884、WO2023 / 284651、US2017-0283397、US2022-006 4126, CN103054869, CN103319466, CN104119280, CN105541806, CN105924362, CN105985265, CN106045862 , CN106045881, CN106432248, CN106478639, CN106831489, CN106928235, CN107033148, CN107174584, CN10 7176927, CN107459476, CN107474011, CN107501169, CN107936022, CN108530302, CN109265462, CN109293 664. CN109535019, CN110204551, CN110478352, CN111072610, CN111454252, CN112110936, CN112409310, C N112920130, CN113087712, CN113105479, CN113264903, CN113582906, CN113599380, CN114502561, CN114805205, CN114805261, KR20190040763 or KR20190040783, each of which is incorporated herein by reference in its entirety (particularly including the compounds described in the Examples section of each of these documents). Therefore, the LSD1 inhibitor may be, for example, a compound disclosed in each of the above-mentioned documents (including, for example, a compound in the Examples section of each of these documents), wherein the compound may be used in a non-salt form or in the form of a pharmaceutically acceptable salt. ,

[0050] In some embodiments, the LSD1 inhibitor is selected from adrenostat, prodromostat, pomadenostat, celidenostat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, vafidinostat, 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile and pharmaceutically acceptable salts thereof (i.e., pharmaceutically acceptable salts of any one of the above compounds).

[0051] Adalestad is a selective and irreversible LSD1 inhibitor. Adalestad is the INN of the compound of the following formula:

[0052]

[0053] [CAS Reg. No. 1431304-21-0], also known as ORY-1001 or (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine. Adalestad has been described, for example, in Example 5 of WO2013 / 057322. Pharmaceutically acceptable salts of adalestad, including hydrochloride salts (particularly adalestad dihydrochloride) are also described in WO2013 / 057322.

[0054] Prodromostat is a reversible LSD1 inhibitor of the formula

[0055]

[0056] [CAS Reg. No. 1821307-10-1], also known as CC-90011, chemical name 4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile. Prodromus has been described in, for example, WO2015 / 168466 and WO2017 / 79670. Also described therein are pharmaceutically acceptable salts thereof, including benzenesulfonates.

[0057] Pomidostat is an irreversible LSD1 inhibitor of the formula

[0058]

[0059] [CAS registration number 1990504-34-1], also known as IMG-7289, chemical name N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazol-1-yl)benzamide. Pomedesophanate has been described in, for example, WO2016 / 130952 and WO2018 / 35259. Its pharmaceutically acceptable salts, including bis-toluenesulfonate, are also described therein.

[0060] Celidenostat is a LSD1 inhibitor of the formula

[0061]

[0062] [CAS Reg. No. 1423715-37-0], also known as SP-2577, chemical name (E)-N'-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide. Celidex has been described in, for example, WO2013 / 025805 and WO2014 / 205213.

[0063] 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid is an irreversible LSD1 inhibitor, which is described, for example, in WO2015 / 123465 and WO2017 / 27678. Pharmaceutically acceptable salts thereof, including p-toluenesulfonate, are also described. The structure of the compound can be described as follows:

[0064]

[0065] 3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide is an irreversible LSD1 inhibitor, which is described, for example, in WO2020 / 047198. Pharmaceutically acceptable salts thereof are also described. The structure of the compound can be described as follows:

[0066]

[0067] Vafidostat is an irreversible LSD1 inhibitor of the following formula:

[0068]

[0069] Also known as ORY-2001, 5-((((1R,2S)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine or (-)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine. Vafidrostatin has been described, for example, in Example 35 of WO2012 / 13728.

[0070] 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile is a LSD1 inhibitor, which is described, for example, in WO2017 / 090756 (or EP3381896A1; see Example 37), WO2021 / 095835, WO2022 / 240886 and WO2023 / 054547. Pharmaceutically acceptable salts of the compound are also described, including benzoate, sorbate, succinate, L-tartrate, hydrochloride, hemifumarate, monofumarate, hemioxalate, monooxalate, methanesulfonate, ethanesulfonate or maleate. A special solid form of the compound is described in WO2022 / 240886. The compound is also referred to herein as "TAS1440". The structure of the compound can be described as follows:

[0071]

[0072] Other examples of LSD1 inhibitors include SYHA1807 or a pharmaceutically acceptable salt thereof or JBI-802 or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the LSD1 inhibitor is selected from adrenaline, prodromalinostat, pomadenostat, celidenostat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile and pharmaceutically acceptable salts thereof.

[0074] In particular, the LSD1 inhibitor can be selected from adrenaline, prodromalinostat, pomadenotstat, celidenotstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide and pharmaceutically acceptable salts thereof.

[0075] In a preferred embodiment, the LSD1 inhibitor is selected from adalest, prolodimstat, pomadestat and pharmaceutically acceptable salts thereof. In some embodiments, the LSD1 inhibitor is prolodimstat or a pharmaceutically acceptable salt thereof (e.g., prolodimstat besylate). In some embodiments, the LSD1 inhibitor is pomadestat or a pharmaceutically acceptable salt thereof (e.g., pomadestat bis-tosylate).

[0076] A particularly preferred LSD1 inhibitor is adrenaline or a pharmaceutically acceptable salt thereof. In some embodiments, adrenaline is used as a dihydrochloride salt (ie, adrenaline dihydrochloride).

[0077] Unless otherwise specifically indicated, any LSD1 inhibitor (e.g., adrenaline) referred to throughout the specification and claims includes such LSD1 inhibitor in non-salt form and any pharmaceutically acceptable salt thereof. When the LSD1 inhibitor is adrenaline, it is preferably used in the form of a pharmaceutically acceptable salt, preferably a hydrochloride, more preferably a dihydrochloride.

[0078] Pharmaceutical preparations

[0079] The LSD1 inhibitor used in the present invention and any pharmaceutical composition containing the LSD1 inhibitor used in the present invention can be administered by any route suitable for the condition to be treated. Exemplary routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, inhalation, intradermal, intrathecal, epidural and infusion techniques), transdermal, rectal, nasal, topical (including oral and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. Preferably, the LSD1 inhibitor (or corresponding pharmaceutical composition) is administered orally.

[0080] The LSD1 inhibitor used in the present invention can be administered in the form of any convenient pharmaceutical composition or formulation, for example as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions / formulations may contain components commonly used in pharmaceutical preparations, such as diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing osmotic pressure, buffers, masking agents, antioxidants and / or other active agents. They may also contain other substances with therapeutic activity or therapeutic value.

[0081] A typical formulation is prepared by mixing an LSD1 inhibitor and one or more pharmaceutically acceptable excipients. Suitable excipients are well known to those skilled in the art and are described in detail in, for example, "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems" (2004) Lippincott, Williams & Wilkins, Philadelphia; "Remington: The Science and Practice of Pharmacy" (2000) Lippincott, Williams & Wilkins, Philadelphia; or "Handbook of Pharmaceutical Excipients" (2005) Pharmaceutical Press, Chicago. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and / or other additives known to provide an elegant appearance of the active agent or to aid in the preparation of the drug product (i.e., medicament).

[0082] For oral delivery, the LSD1 inhibitor can be incorporated into a formulation comprising a pharmaceutically acceptable carrier, such as a binder (e.g., gelatin, cellulose, or tragacanth), an excipient (e.g., starch or lactose), a lubricant (e.g., magnesium stearate or silicon dioxide), a disintegrant (e.g., alginate, Primogel, or corn starch), and a sweetener or flavoring agent (e.g., glucose, sucrose, saccharin, methyl salicylate, or mint). The formulation can be delivered orally, for example, in the form of encapsulated gelatin capsules or compressed tablets. Capsules and tablets can be prepared by any conventional technique. Capsules and tablets can also be coated with a variety of coating agents known in the art to modify the flavor, taste, color, and shape of the capsules and tablets. In addition, a liquid carrier, such as a fatty oil, can also be included in the capsule.

[0083] Suitable oral formulations may also be in the form of suspensions, syrups, chewing gums, wafers, elixirs, and the like. Conventional agents for modifying the flavor, taste, color, and shape of a particular form may also be included if desired. In addition, to facilitate administration via an enteral feeding tube to individuals who are unable to swallow, the active compound may be dissolved in an acceptable lipophilic vegetable oil vehicle, such as olive oil, corn oil, or safflower oil.

[0084] LSD1 inhibitors can also be administered parenterally in the form of solutions or suspensions or in a lyophilized form that can be converted into solutions or suspensions before use. In such preparations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants and antioxidants can all be included. For example, useful components include sodium chloride, acetate, citrate or phosphate buffers, glycerol, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. Parenteral preparations can be stored in any conventional containers, such as vials and ampoules.

[0085] Subcutaneous implantation for sustained release of LSD1 inhibitors may also be a suitable route of administration. This requires surgical intervention to implant the LSD1 inhibitor in any suitable formulation into the subcutaneous space, for example, beneath the anterior abdominal wall. See, for example, Wilson et al. (1984) J. Clin. Psych. 45: 242-247. Hydrogels can be used as carriers for sustained release of LSD1 inhibitors. Hydrogels are well known in the art. They are typically made by cross-linking high molecular weight biocompatible polymers into a mesh structure that swells into a gel-like material in water. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purposes of the present invention, hydrogels made of polyethylene glycol, collagen or poly (glycolic acid-co-L-lactic acid) may be useful; see, for example, Phillips et al. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

[0086] Pharmaceutical compositions such as oral and parenteral compositions can be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, "unit dosage form" refers to physically discrete units suitable as unit dosages for administration to individuals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers.

[0087] Suitable oral dosage forms of adrenaline are disclosed, for example, in WO2019 / 211491.

[0088] In particular, adrenaline can be provided in the form of a solid oral dosage form, such as a tablet or capsule. Alternatively, adrenaline can also be provided in the form of an oral liquid composition, in particular an oral solution, such as an oral aqueous solution (corresponding oral solutions, including oral aqueous solutions, can be prepared, for example, from a powder for reconstitution). As explained above, adrenaline is preferably used in the form of adrenaline dihydrochloride.

[0089] For the treatment of MPNST, LSD1 inhibitors (or corresponding pharmaceutical compositions) may be administered in any suitable manner, as determined by those skilled in the medical field. Suitable dosages and suitable duration and frequency of administration may vary within wide limits and may be determined by factors such as the individual condition, the specific type and severity of the disease, the specific form of the active ingredient, and the method of administration. Typically, suitable dosages and administration regimens provide an amount of LSD1 inhibitor sufficient to provide a therapeutic benefit, such as improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free survival and / or overall survival, or a reduction in symptom severity, or any other objectively identifiable improvement of concern to clinicians. Therapeutically effective doses can often be estimated or inferred using experimental models, such as dose-response curves from in vitro or animal model test systems or human clinical trials.

[0090] Suitable dosages and dosing regimens for LSD1 inhibitors depend on the specific LSD1 inhibitor used, its LSD1 inhibitory potency, its pharmacokinetic properties and other factors, as is well known to those skilled in the art.

[0091] Adalestad is a highly effective active pharmaceutical ingredient (HPAPI). Therefore, the expected daily dose is very low, for example, less than 1 mg / day. Therefore, the drug load in the pharmaceutical preparation (including, for example, a solid oral form) is also generally very low (for example, less than 1 mg API / 100 mg solid oral form). Generally, for adult individuals (i.e., individuals aged 18 or above), in the case of oral administration (for example, as tablets, capsules or oral solutions, including oral aqueous solutions), the daily dose of Adalestad of about 50 μg-about 300 μg, preferably about 75 μg-about 300 μg (for example, about 75 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 225 μg, about 250 μg, about 275 μg or 300 μg or any range between any two of the above daily doses) as described herein should be suitable, however, when necessary, these restrictions can be adjusted. For example, the above dosages may be reduced for pediatric use, particularly for oral administration to human subjects younger than 18 years (e.g., 0-2 years, 2-12 years, or 12 to younger than 18 years). As used herein, the term "μg" (or "ug") refers to micrograms.

[0092] In some embodiments, the LSD1 inhibitor is adrenaline (or a pharmaceutically acceptable salt thereof, such as adrenaline dihydrochloride), and is administered five days per week on / two days off (5 / 2).

[0093] In some embodiments, the LSD1 inhibitor is adrenaline (or a pharmaceutically acceptable salt thereof, such as adrenaline dihydrochloride), and is orally administered to adult individuals at a daily dose of about 50 μg to about 300 μg, preferably about 75 μg to about 300 μg (e.g., about 100 μg to about 300 μg), five days a week / two days off (5 / 2). The adrenaline doses reflected herein refer to the corresponding amount of adrenaline free base. In some embodiments, adrenaline is orally administered at a daily dose of about 75 μg, five days a week / two days off (5 / 2). In some embodiments, adrenaline is orally administered at a daily dose of about 100 μg, five days a week / two days off (5 / 2). In some embodiments, adrenaline is orally administered at a daily dose of about 150 μg, five days a week / two days off (5 / 2). In some embodiments, adrenaline is orally administered at a daily dose of about 200 μg, five days a week, two days off (5 / 2). In some embodiments, adrenaline is orally administered at a daily dose of about 250 μg, five days a week, two days off (5 / 2). In some embodiments, adrenaline is orally administered at a daily dose of about 300 μg, five days a week, two days off (5 / 2). As explained above, these doses can be reduced for pediatric use.

[0094] Combination therapy

[0095] The LSD1 inhibitors used in the present invention can be administered in monotherapy (e.g., without the need for concurrent administration of any other therapeutic agent or without the need for concurrent administration of any other anticancer agent). Thus, the present invention relates to LSD1 inhibitors (or pharmaceutical compositions comprising LSD1 inhibitors and optionally one or more pharmaceutically acceptable excipients) for use in monotherapy treatment of MPNST. The present invention also relates to corresponding methods and uses for monotherapy treatment of MPNST.

[0096] However, the LSD1 inhibitor may also be administered in combination with one or more additional therapeutic agents, in particular one or more additional anticancer agents. If the LSD1 inhibitor is used in combination with an additional anticancer agent, the dose of each compound may differ from the dose when the corresponding compound is used alone, in particular, lower doses of either or both compounds may be used.

[0097] The combination of an LSD1 inhibitor and one or more additional therapeutic agents (e.g., one or more additional anti-cancer agents) may be contained in a single pharmaceutical formulation or in separate pharmaceutical formulations. The LSD1 inhibitor and the additional therapeutic agent are administered simultaneously / concomitantly, or the LSD1 inhibitor and the additional therapeutic agent are administered sequentially / separately. If administered sequentially, either the LSD1 inhibitor or the one or more additional therapeutic agents may be administered first. If administered simultaneously, the one or more additional therapeutic agents may be contained in the same pharmaceutical formulation as the LSD1 inhibitor, or they may be administered in two or more different / separate pharmaceutical formulations. It will be appreciated that administering the LSD1 inhibitor and the additional therapeutic agent in separate pharmaceutical formulations may be convenient, for example, if the different active agents are administered by different routes and / or using different administration plans / schemes.

[0098] In addition, LSD1 inhibitors can also be administered in combination with physical therapy, in particular radiotherapy. The present invention also relates to the combined use of LSD1 inhibitors with one or more additional therapeutic agents (in particular one or more additional anticancer agents) and physical therapy (in particular radiotherapy). Physical therapy (or radiotherapy) can be started before, after or simultaneously with the administration of the LSD1 inhibitor (e.g. about 1-72 hours before or after the administration of the LSD1 inhibitor).

[0099] Therefore, the present invention relates to LSD1 inhibitors for use in combination with one or more additional therapeutic agents, in particular one or more additional anticancer agents, and / or in combination with radiotherapy for the treatment of MPNST. The present invention also relates to pharmaceutical compositions comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients for use in combination with one or more additional therapeutic agents, in particular one or more additional anticancer agents, and / or in combination with radiotherapy for the treatment of MPNST. The present invention also relates to LSD1 inhibitors (or pharmaceutical compositions comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients) for use in the treatment of MPNST, wherein the LSD1 inhibitor (or pharmaceutical composition comprising a LSD1 inhibitor) is administered in combination with one or more additional therapeutic agents, in particular one or more additional anticancer agents, and / or in combination with radiotherapy. The present invention also relates to LSD1 inhibitors (or pharmaceutical compositions comprising LSD1 inhibitors and optionally one or more pharmaceutically acceptable excipients) for use in the treatment of MPNST, wherein the LSD1 inhibitor (or pharmaceutical composition comprising LSD1 inhibitor) is used in combination with one or more additional therapeutic agents (particularly one or more additional anticancer agents) and / or in combination with radiotherapy. The present invention also relates to: (i) an anticancer agent for the treatment of MPNST in combination with a LSD1 inhibitor; (ii) an anticancer agent for the treatment of MPNST, wherein the anticancer agent is administered in combination with a LSD1 inhibitor; or (iii) an anticancer agent for the treatment of MPNST, wherein the anticancer agent is used in combination with a LSD1 inhibitor.

[0100] The present invention also provides a method for treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor (or a therapeutically effective amount of a pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients) in combination with a therapeutically effective amount of one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and / or in combination with radiotherapy.

[0101] Furthermore, the present invention relates to the use of LSD1 inhibitors in combination with one or more additional therapeutic agents, in particular one or more additional anticancer agents, and / or in combination with radiotherapy in the treatment of MPNST. The present invention also relates to the use of an anticancer agent in combination with a LSD1 inhibitor in the treatment of MPNST.

[0102] The present invention also relates to the use of a LSD1 inhibitor in combination with one or more additional therapeutic agents, in particular one or more additional anticancer agents, and / or in combination with radiotherapy in the preparation of a medicament (or pharmaceutical composition) for the treatment of MPNST. The present invention also relates to the use of a combination of an anticancer agent and a LSD1 inhibitor in the preparation of a medicament for the treatment of MPNST. The present invention also relates to the use of a LSD1 inhibitor in combination with one or more additional anticancer agents in the preparation of a medicament for the treatment of MPNST, wherein the medicament comprises the LSD1 inhibitor and the additional anticancer agent in the same pharmaceutical preparation or in separate pharmaceutical preparations. The present invention also relates to the use of a LSD1 inhibitor in the preparation of a medicament for the treatment of MPNST, wherein the medicament is prepared for use in combination (or for combined use) with one or more additional therapeutic agents, in particular one or more additional anticancer agents, and / or with radiotherapy. The present invention also relates to the use of an anticancer agent in the preparation of a medicament for the treatment of MPNST, wherein the medicament is prepared for use in combination (or for combined use) with a LSD1 inhibitor.

[0103] The present invention also provides a combination product comprising a LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anticancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in the treatment of MPNST. Thus, the LSD1 inhibitor and the additional therapeutic agent (particularly the additional anticancer agent) may be present in a single pharmaceutical formulation (i.e. in the same pharmaceutical formulation), or they may each be provided in different (separate) pharmaceutical formulations.

[0104] The present invention also provides a pharmaceutical composition comprising a LSD1 inhibitor in combination with one or more additional therapeutic agents (particularly one or more additional anticancer agents) and one or more pharmaceutically acceptable excipients for use in the treatment of MPNST.

[0105] The present invention also provides an article of manufacture (or kit) comprising a LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in the treatment of MPNST.

[0106] The present invention also provides a method for treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the above-mentioned combination product, pharmaceutical composition or preparation. In particular, the present invention provides a method for treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a combination product, which comprises a LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anticancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations. The present invention also provides a method for treating MPNST in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor and a therapeutically effective amount of one or more additional therapeutic agents (particularly one or more additional anticancer agents).

[0107] The present invention also provides the use of a combination comprising an LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anticancer agents) in the preparation of a medicament (or pharmaceutical composition) for the treatment of MPNST. The present invention also provides the use of a combination comprising an LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anticancer agents) in the treatment of MPNST.

[0108] The anticancer agent (in particular the “anticancer agent” or “one or more additional anticancer agents” referred to in any of the above paragraphs herein) can be selected from, for example, a MEK inhibitor (in particular a MEK1 and / or MEK2 inhibitor; for example selumetinib), a Pi3K inhibitor (for example cupranisib), an mTOR inhibitor (for example temsirolimus), an ERK inhibitor (in particular an ERK1 and / or ERK2 inhibitor; for example uritinib), a kRAS inhibitor (for example sotolacib), an EGFR inhibitor (for example lapatinib), a cKIT inhibitor (for example imatinib), a proteasome inhibitor (for example bortezomib), a DNA intercalator (for example doxorubicin), a RAF inhibitor (in particular a BRAF inhibitor; for example sorafenib), a VEGF inhibitor (for example VEGF), a VEGF inhibitor (for example VEGF), a VEGF inhibitor (for example VEGF), a VEGF inhibitor (for example VEGF), a VEGF inhibitor (for example VEGF), a VEGF inhibitor (for example VEGF), a VEGF inhibitor (for example GFR inhibitors (e.g., cabozantinib), ALK inhibitors (e.g., crizotinib), glutaminase inhibitors (e.g., tiraginostat), JAK inhibitors (or Janus kinase inhibitors; e.g., tofacitinib), PLK1 inhibitors (e.g., vorinostat), Bcl2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), HSP90 inhibitors (e.g., onaspib), Wnt / β-catenin pathway inhibitors (e.g., OMP-18R5), Aurora kinase inhibitors (e.g., alecetin), MDM2 inhibitors (e.g., eremidine), CDK4 / 6 inhibitors (e.g., abemaciclib), YAP / TAZ pathway inhibitors (e.g., pazopanib), SOS inhibitors (e.g., BI 1701963), Grb2 inhibitors (e.g. BP1001), BET inhibitors (particularly including BRD4 inhibitors; e.g. GSK1210151A), AKT inhibitors (e.g. patasertib), MNK inhibitors (e.g. ETC-206), NTRK inhibitors (e.g. entrectinib), SPH2 inhibitors (e.g. JAB-3068) and PP2A inhibitors (e.g. LB100).

[0109] MEK inhibitors can be, for example, selumetinib, trametinib, cobimetinib, bimetinib, midametinib, pimasertib, refactinib, zanotinib, ivometinib, HL-085, FCN-159, TAK-733, or a pharmaceutically acceptable salt of any one of these active agents. Pi3K inhibitors can be, for example, cupanisib, apellisib, idelalisib, duvilisib, erbulisib, bupallisib, zanalisib, limplisib, pasalisib, lanilisib, pasalisib, inarlisib, serabelisib, pitilisib, taselisib, tenalisib, eigalisib, GSK2636771, MEN1611, AMG-319, or a pharmaceutically acceptable salt of any one of these active agents. The mTOR inhibitor may be, for example, temsirolimus, everolimus, sirolimus, or a pharmaceutically acceptable salt of any of these agents. The ERK inhibitor may be, for example, uritinib or a pharmaceutically acceptable salt thereof. The kRAS inhibitor may be, for example, sotolasib, adagracib, or a pharmaceutically acceptable salt of any of these agents. The EGFR inhibitor may be, for example, lapatinib, gefitinib, erlotinib, osimertinib, afatinib, or a pharmaceutically acceptable salt of any of these agents. The cKIT inhibitor may be, for example, imatinib, sorafenib, lapatinib, sunitinib, or a pharmaceutically acceptable salt of any of these agents. The proteasome inhibitor may be, for example, bortezomib, carfilzomib, ixazomib, or a pharmaceutically acceptable salt of any of these agents. The DNA intercalator may be, for example, doxorubicin, daunorubicin, epirubicin, idarubicin, or a pharmaceutically acceptable salt of any of these agents. RAF inhibitors can be, for example, sorafenib, conafenib, dabrafenib, vemurafenib or a pharmaceutically acceptable salt of any of these active agents. VEGFR inhibitors can be, for example, cabozantinib, axitinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib or a pharmaceutically acceptable salt of any of these active agents. ALK inhibitors can be, for example, crizotinib, alectinib, ceritinib or a pharmaceutically acceptable salt of any of these active agents. Glutaminase inhibitors can be, for example, tiragist or a pharmaceutically acceptable salt thereof. JAK inhibitors can be, for example, tofacitinib, ruxolitinib, upadatinib, abrocitinib or a pharmaceutically acceptable salt of any of these active agents. PLK1 inhibitors can be, for example, volasertib, avensetib, regsetib, BI 2536 or a pharmaceutically acceptable salt of any of these active agents. The Bcl2 inhibitor can be, for example, venetoclax, navitoclax, obatolac, or a pharmaceutically acceptable salt of any of these agents.HDAC inhibitors can be, for example, vorinostat, belinostat, panobinostat, romidepsin, pranostat, ronostat, quinostat, abestat, reminostat, givista, entinostat and moxistat or a pharmaceutically acceptable salt of any one of these active agents. HSP90 inhibitors can be, for example, onaspi, lumispi, gatoraspi, geldanamycin, IPI-504, tasipilomycin, aspiramycin or a pharmaceutically acceptable salt of any one of these active agents. Wnt / β-catenin pathway inhibitors can be, for example, OMP-18R5, OMP-54F28, OTSA101, SAH-BCL9, XAV939, IWR1, JW74, J01-017a, PKF115-584, PKF118-310, NCB-0846, LGK974, CWP232291, PRI-724, sulindac, vismodegib, gladegib, or a pharmaceutically acceptable salt of any of these active agents. Aurora kinase inhibitors can be, for example, alisetin, tauzasetib, balacetib, darusetib, or a pharmaceutically acceptable salt of any of these active agents. MDM2 inhibitors can be, for example, Arimidine, Idanulin, RO5045337, RO5503781, AMG232, CGM097, SAR405838, MK-8242, ALRN-6924, or a pharmaceutically acceptable salt of any of these active agents. CDK4 / 6 inhibitors can be, for example, abemaciclib, ribociclib, palbociclib, or a pharmaceutically acceptable salt of any of these active agents. YAP / TAZ pathway inhibitors can be, for example, K-975, TED-347, pazopanib, or a pharmaceutically acceptable salt of any of these active agents. SOS inhibitors can be, for example, BI 1701963, BI 3406, BAY-293, or a pharmaceutically acceptable salt of any of these active agents. Grb2 inhibitors can be, for example, BP1001, CGP78850, CGP85793, or a pharmaceutically acceptable salt of any of these active agents. The BET inhibitor can be, for example, ABBV-075, ABBV-744, AZD5153, BAY1238097, CPI-203, CPI-0610, GSK1210151A (or I-BET151), GSK1324726A (I-BET 726), GSK525762 (or I-BET 762), JQ1, LY294002, MS 436, MS645, MT-1, orinone, OTX-015, RVX-208, TEN-010, or a pharmaceutically acceptable salt of any of these active agents.AKT inhibitors can be, for example, patasert, uroset, afloset, MK-2206, triciribine, lactoquinomycin, AZD5363, milanset, capiset or a pharmaceutically acceptable salt of any of these active agents. MNK inhibitors can be, for example, ETC-206, SEL-201, BAY1143269, tomivoset, CGP57380 or a pharmaceutically acceptable salt of any of these active agents. NTRK inhibitors can be, for example, entrectinib, larotrectinib or a pharmaceutically acceptable salt of any of these active agents. SPH2 inhibitors can be, for example, JAB-3068, TNO155, SHP099, RMC-4550, IACS-13909 or a pharmaceutically acceptable salt of any of these active agents. The PP2A inhibitor can be, for example, LB100, cantharidin, cantharidic acid, estradiol phosphate, forsitracin, or a pharmaceutically acceptable salt of any of these active agents. Any of the above anticancer agents can generally be used in a non-salt form or in the form of a pharmaceutically acceptable salt. The present invention particularly and separately relates to each of the LSD1 inhibitors described herein in combination with each of the above anticancer agents.

[0110] As described above, the one or more additional therapeutic agents used in combination with the LSD1 inhibitor of the invention may be (or may include) one or more additional anticancer agents. Alternatively or in addition, the one or more additional therapeutic agents may also include an antiemetic. Therefore, the present invention also relates to LSD1 inhibitors for the treatment of MPNST in combination with one or more additional anticancer agents and in combination with an antiemetic (and optionally in combination with radiotherapy); the present invention also relates to corresponding methods and uses (including all methods and uses described above) comprising the combined administration of an LSD1 inhibitor, one or more additional anticancer agents and an antiemetic. The antiemetic may be, for example, a 5-HT3 antagonist (or "setron"), such as palonosetron (optionally in combination with netupitant), ramosetron, alosetron, ondansetron, tropisetron, granisetron, dolasetron, azasetron, bemisetron, cilansetron, lelisetron, licarsetron or zatosetron; olanzapine; a corticosteroid, such as methylprednisone or dexamethasone; or prochlorperazine.

[0111] Products

[0112] A pharmaceutical composition (or formulation) of the invention may be included in a container, pack, or dispenser together with instructions for administration.

[0113] Thus, in another embodiment, the invention provides an article of manufacture comprising a LSD1 inhibitor or a pharmaceutical composition comprising a LSD1 inhibitor for use in treating an MPNST as described herein.

[0114] In some embodiments, an article of manufacture comprises a container and a pharmaceutical composition as described herein for use of the invention.

[0115] In some embodiments, the present invention provides an article of manufacture (or kit) comprising a container and a combination product (as described above) for use in treating MPNST. The present invention also provides an article of manufacture (or kit) comprising: (i) a first container comprising a LSD1 inhibitor, (ii) a second container comprising another anticancer agent (as described above), and (iii) optionally one or more additional containers comprising one or more additional anticancer agents for use in treating MPNST.

[0116] The article can also include a label or instructions. The term "instructions" is used to refer to instructions generally included in the commercial packaging of therapeutic products, which include information about the indications, usage, dosage, administration, contraindications and / or warnings for using such therapeutic products. Suitable containers include, for example, blister packages, bottles, vials, syringes, etc. The container can be made of a variety of materials, such as glass or plastic. The container can hold a composition or preparation that effectively treats a condition, and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). The label or instructions indicate that the composition is used to treat a selected condition, particularly MPNST. Alternatively or in addition, the article can also include a second container, which includes a pharmaceutically acceptable buffer, such as antibacterial water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It can also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles and syringes.

[0117] The article of manufacture or kit may also contain instructions for combined administration of one or more other anticancer agents (as described above). For example, if the kit contains a first pharmaceutical composition / formulation containing an LSD1 inhibitor and a second pharmaceutical composition / formulation containing an additional anticancer agent, the kit may also contain instructions for administering the first and second pharmaceutical compositions / formulations simultaneously, sequentially or separately to an individual in need thereof.

[0118] In another embodiment, the preparation is suitable for delivering a solid oral form of an LSD1 inhibitor, such as a tablet or capsule. Such preparations preferably include multiple unit doses. Such preparations may include a card with the doses arranged in the order of intended use. An example of such a preparation is a "blister pack". Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, a memory aid may be provided, for example in the form of numbers, letters or other markings, or in the form of a calendar insert, to specify the dates in the treatment plan when the doses can be administered.

[0119] According to one embodiment, the article of manufacture or kit may comprise: (i) a first container comprising an LSD1 inhibitor; (ii) a second container comprising an additional anticancer agent; and optionally (iii) a third container comprising an additional anticancer agent, wherein the anticancer agent in the third container is different from the anticancer agent in the second container. Alternatively or in addition, the kit may comprise an additional container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. It may also contain other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and / or syringes.

[0120] If the article of manufacture or kit comprises a combination of an LSD1 inhibitor and a combination of an additional anticancer agent, the kit may comprise containers for containing the separate compositions, such as divided bottles or divided foil packets; however, the separate compositions may also be contained within a single, undivided container. Typically, the kit comprises instructions for administration of the separate components. The kit format is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosage intervals, or when the prescribing clinician or veterinarian desires to titrate the individual components of the combination.

[0121] definition

[0122] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0123] The following definitions apply throughout the specification and claims, unless specifically stated otherwise.

[0124] For the purposes of the present invention, "individuals" (or "patients") include humans and other animals, particularly mammals. Therefore, the methods and uses of the present invention are suitable for human therapy and veterinary applications. In preferred embodiments, the individual (or patient) is a mammal (e.g., a human or non-human mammal), and most preferably the individual is a human (e.g., male or female). Human individuals can be of any age, including, for example, 0 to 2 years old, 2 to 12 years old, 12 to 18 years old, or 18 years old or older.

[0125] As used herein, the terms "treatment", "treating" and the like generally refer to obtaining a desired pharmacological and / or physiological effect. This includes partial or complete cure or amelioration of a disease (i.e., MPNST) and / or symptoms or adverse reactions attributable to the disease, or partial or complete arrest of the progression of a disease and / or symptoms or adverse reactions attributable to the disease. As used herein, the term "treatment" encompasses any treatment of an individual disease (i.e., MPNST), including but not limited to inhibiting MPNST, i.e., arresting, delaying or slowing its development / progression; or alleviating MPNST, i.e., causing its (complete or partial) regression, alleviation, correction or slowing. The present invention particularly and specifically relates to each of these treatment modalities.

[0126] As used herein, the term "therapeutically effective amount" or "effective amount" of a compound of the invention (particularly an LSD1 inhibitor) refers to an amount sufficient to produce a desired biological effect (e.g., a therapeutic effect or benefit) in an individual. Thus, when administered to an individual suffering from or susceptible to a disease, a therapeutically effective amount of a compound may be an amount sufficient to treat the disease (i.e., MPNST) and / or delay the onset or progression of the disease, and / or alleviate one or more symptoms of the disease. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0127] The term "pharmaceutically acceptable" refers to the nature of materials useful in preparing pharmaceutical compositions, being generally safe, non-toxic, neither biologically nor otherwise undesirable, and acceptable for veterinary and / or human pharmaceutical use.

[0128] As used herein, "pharmaceutically acceptable salts" are intended to refer to salts that retain the biological effectiveness of the free acids and / or bases of the specified compound and are not biologically or otherwise undesirable. A compound may have one or more sufficiently acidic or sufficiently basic functional groups, or both, and thus react with any of a variety of inorganic or organic bases and inorganic or organic acids to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those prepared by reacting a compound described herein (particularly an LSD1 inhibitor, such as adrenaline) with an inorganic or organic acid, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitrate, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, Chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate (or mesylate), ethanesulfonate, propanesulfonate, benzenesulfonate (or besylate), toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, pyruvate, stearate, ascorbate or salicylate. When the compound (particularly the LSD1 inhibitor) carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, etc. Pharmaceutically acceptable salts are well known in the art (see, for example, Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, 2002, and references cited therein, all of which are incorporated herein by reference).

[0129] The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and refer to a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient (particularly a LSD1 inhibitor) and one or more pharmaceutically acceptable excipients, which is administered to an individual (e.g., a human) in need thereof.

[0130] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and is non-toxic to the individual to whom it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, etc., used to formulate a pharmaceutical product. They are generally safe for administration to humans according to established government standards, including those promulgated by the U.S. Food and Drug Administration and / or the European Medicines Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

[0131] As used herein, the term "inhibitor" refers to a compound that competes with, reduces, blocks, inhibits, eliminates, or in any way interferes with the binding of a specific ligand to a specific receptor or enzyme, and / or a compound that reduces, prevents, inhibits, eliminates, or interferes with the activity or function of a specific protein (e.g., a receptor or enzyme) in any way.

[0132] As used herein, "small molecule" refers to an organic compound having a molecular weight equal to or less than 900 Da (Daltons), preferably less than 500 Da. The molecular weight is the mass of the molecule and is calculated as the sum of the atomic weights of each constituent element multiplied by the number of atoms of that element in the molecular formula.

[0133] As used herein, the term "comprising" (or "comprise", "comprises", "contain", "contains" or "containing") has the meaning of "comprising, inter alia", i.e., "comprising, in addition to other optional elements, ...", unless otherwise expressly indicated or indicated to the contrary. In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprises B and C" has the meaning of "A comprises, inter alia, B and C", where A may include other optional elements (e.g., "A comprises B, C, and D" would also be covered), but the term also includes the meaning of "A consists essentially of B and C" and the meaning of "A consists of B and C" (i.e., A does not contain other elements other than B and C).

[0134] As used herein, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0135] The term "about" or "approximately" refers to the acceptable error of a particular value determined by one of ordinary skill in the art, which depends in part on how to measure or determine the value. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. References to any numerical value or range provided in connection with the term "about" also include the corresponding specific values ​​or ranges involved.

[0136] In addition, it should be understood that wherever a numerical range is provided / described herein, the present invention specifically provides all values ​​and sub-ranges encompassed by the corresponding numerical range. Therefore, the present invention specifically and individually relates to each value falling within the numerical range described herein, and each and any sub-range encompassed by the numerical range described herein.

[0137] This specification describes various compounds by their chemical formulas and corresponding chemical names. If there is a conflict between any chemical formula and the corresponding chemical name shown herein, the present invention specifically and solely relates to the compound defined by the chemical formula and the compound defined by the chemical name.

[0138] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Example

[0139] The following examples are provided to illustrate the present invention. They should not be considered to limit the scope of the present invention, but are merely representative thereof.

[0140] Example 1: Effect of LSD1 inhibitors in MPNST survival assay

[0141] 1.1 Experimental design

[0142] The mycoplasma-free MPNST cell line (see Table 1) was seeded at an optimal cell density in 50 μL / well of complete medium (DMEM high glucose supplemented with 1× GlutaMAX TM, 1× sodium pyruvate and 10% fetal bovine serum (FBS, ThermoFisher) to ensure logarithmic growth throughout the assay (see Table 1). The day after plating, 50 μL of medium containing 9 serial dilutions (1:3) of 2× concentrated adrenaline (LSD1 inhibitor; used as the dihydrochloride salt) was added to the cells to obtain 100 μL of cells, with each dilution treated with 1× concentrated compound. Etoposide (a topoisomerase II / DNA synthesis inhibitor) was also included as a positive control for this assay. In addition, from the MPNST cell line panel, two cell lines (sNF96.2 and sNF02.2) were selected to evaluate the effects of other LSD1 inhibitors, namely, pomadeletastat (bis-tosylate) and prolodreletastat (besylate). Each experimental condition was tested in technical triplicate, including wells with medium alone and vehicle-treated controls for background correction and calibration, respectively. After treatment, cells were incubated at 37°C in a humidified and controlled 5% CO2 atmosphere for 72 hours. At this time, compound and medium refreshment was performed by adding 50 μL of medium supplemented with 1× concentrated compound at each corresponding dilution. The MTT assay (Sigma-Aldrich) or AlamarBlu was used according to the manufacturer's instructions. TM Cells were incubated for an additional 72 hours (6 days total) before assessing cell viability using the Cell Viability Reagent (Life Technologies). Background was calculated as the mean of the media-only controls and subtracted from each data point. The mean of background-corrected triplicates was calculated and calibrated by the mean of the vehicle-treated controls (equivalent to 100% viability). GraphPad Data were analyzed using GraphPad Software, version 9.0.1 (GraphPad Software, Inc., La Jolla, CA / USA) to calculate the best-fit curve and EC 50 value (equivalent to the concentration of compound that achieves half (50%) of the maximal effect; lower EC 50 Values ​​thus indicate greater efficacy).

[0143] Cell lines Cell density (cells / well) MPNST-SP-01 1000 MPNST-NF1-08 8000 MPNST-NF1-09 1000 MPNST-NF1-18b 500 MPNST-SP-10 4000 ST88-14 2000 NMS-2 2000 S462 1000 90-8TL 2000 HS-PSS 2000 sNF02.2 1000 sNF96.2 8000

[0144] Table 1: Cell lines used and their corresponding seeding densities

[0145] 1.2 Results

[0146] A group of 12 MPNST cell lines were used to evaluate the effect of the LSD1 inhibitor adrenaline on the viability of MPNST cells after 6 days of treatment, and etoposide was used as a positive control for this assay. In order to reliably reflect the situation in the clinical setting in in vitro experiments, where MPNST patients are characterized by significant genomic heterogeneity, a group of different types of MPNST cell lines were used. This group includes MPNST immortal cell lines and MPNST cell lines derived from patients. In addition, some MPNST cell lines are associated with neurofibromatosis type I, while others are sporadic, and in both cases, the mutation status of NF1, CDKN2A and PRC2 varies in the genomic background. An overview of its characteristics is provided in Table 2 below.

[0147]

[0148]

[0149] Table 2: Overview of MPNST cell groups

[0150] *The patient-derived MPNST-NF1-18b cell line was initially classified as a sporadic MPNST cell line and named MPNST-SP-09b. After subsequent analysis, this cell line was confirmed to be a neurofibromatosis type I-associated MPNST cell line and renamed MPNST-NF1-18b.

[0151] It has been reported that LSD1 inhibitors such as adrenaline exert their therapeutic effects by inducing cancer cell differentiation and inhibiting cancer cell proliferation rather than by killing cancer cells (Sacilotto N et al., ACS Pharmacol Transl Sci, 2021, 4(6):1818-34, doi:10.1021 / acsptsci.1c00223). Consistent with this, a reduction of more than 30% in cancer cell survival reflects the effective therapeutic effect of the corresponding LSD1 inhibitor. Therefore, in this experiment, the responses obtained after treatment with LSD1 inhibitors were divided into the following three groups: (1) strong response (survival rate reduction>30%); (2) moderate response (survival rate reduction>15% and <30%); (3) low response (survival rate reduction<15%). Table 3 summarizes the EC obtained for etoposide (positive control for this assay) and adrenaline 50 Values, and classification according to decreased survival after LSD1 inhibitor treatment.

[0152]

[0153]

[0154] Table 3: Effects of etoposide (positive control for this assay) and the LSD1 inhibitor adrenostat on cell viability in a panel of MPNST cell lines

[0155] Despite the vast genomic and mutational variation within the panel of MPNST cell lines tested, it was apparent that 8 of the 12 cell lines responded well to treatment with LSD1 inhibitors. Thus, after 6-days of adrenaline treatment, 3 of the 12 cell lines (25%) had a significant decrease in survival, and 5 of the 12 cell lines (41.67%) showed a moderate decrease in survival. Notably, specifically responsive cell lines included both NF1-associated and sporadic (non-NF1-associated) MPNST cell lines, suggesting that treatment with LSD1 inhibitors (e.g., adrenaline) achieves a therapeutic effect in a broad subset of MPNST patients, including NF1-associated MPNST as well as MPNST unrelated to NF1. Furthermore, in the moderately- and strongly-responsive cell lines (66.67% in total), adrenaline exhibited subnanomolar EC 50 values ​​(see Table 3), indicating that even very low doses have clinically relevant therapeutic effects.

[0156] The effect of LSD1 inhibitors on the viability of MPNST cells was further tested using two additional LSD1 inhibitors, namely, pomadestat and prolodrumostat. Pomadestat, like adalrestat, is an irreversible LSD1 inhibitor, while prolodrumostat is a reversible LSD1 inhibitor. Cell viability was assessed after 6-day treatment in sNF96.2 and sNF02.2 cell lines according to the above method (see Table 4). As shown in Table 4 (and for adalrestat, in Table 3 above), the results obtained thus clearly show that all three LSD1 inhibitors are effective against MPNST, regardless of whether they are irreversible or reversible LSD1 inhibitors.

[0157]

[0158] Table 4: Effects of different LSD1 inhibitors on cell viability of sNF96.2 and sNF02.2 cell lines

[0159] Among the tested LSD1 inhibitors, adrenaline showed the highest efficacy (lowest EC 50 ).

[0160] These results suggest that LSD1 inhibitors, including irreversible LSD1 inhibitors (eg, adrenostat and pomadestat) as well as reversible LSD1 inhibitors (eg, prolostat) are advantageously effective in treating MPNST and can be used in widely different MPNST patient subpopulations.

[0161] Example 2: Method for determining the synergistic effect between LSD1 inhibitors and MEK inhibitors in MPNST cell lines Matrix determination

[0162] 2.1 Experimental design

[0163] 2.1.1 Matrix survival assay (6 days)

[0164] according to Figure 1 Each matrix assay is distributed on 2 plates in a 9 × 9 format, or as shown in Figure 2 The scheme illustrated in , distributed on 1 plate in a 5 x 5 format. The LSD1 inhibitor adrenaline was added in increasing concentrations from top to bottom, and the MEK inhibitor selumetinib was added in increasing concentrations from left to right.

[0165] For this assay, cells were seeded in 96-well plates at the optimal density specified in Example 1 in 50 μL of culture medium; wells at the edge of the plate were filled with 100 μL of medium only for background correction. Each of the two compounds in the combination was added at a 4× concentration in 25 μL, resulting in a final volume of 100 μL for each dilution and a final concentration of 1× (DMSO% < 0.5%). For the 9×9 matrix, compounds were added in a 1:2 serial dilution, while for the 5×5 matrix, compounds were added in a 1:5 serial dilution, so that in both cases the concentration range covered the full dose-response curve. As Figure 1 and 2 As shown in , the matrix was designed so that the expected EC 50 The values ​​are centered horizontally and vertically on the matrix. In this way, the holes on the diagonal of the plate correspond to a fixed EC value between the two compounds. 50 In a 9×9 matrix, the first and last rows of plate #1 are repeated in plate #2 (e.g. Figure 1 The EC values ​​of the compounds tested in the matrix assay were previously obtained by the single agent assay as detailed in Example 1. 50 Values, and for Adalest, as shown in Table 3.

[0166] After treatment, cells were incubated at 37°C in a humidified and controlled 5% CO2 atmosphere for 72 hours. At this time, compound and medium refreshment was performed by adding 50 μL of medium supplemented with 1× concentrated compound at each corresponding dilution. Cell viability was assessed in 2 biological replicates and the MTT assay (Sigma-Aldrich) or AlamarBlue was used according to the manufacturer's instructions. TMCells were incubated for an additional 72 hours (6 days total) before adding the cell viability reagent (Life Technologies). Background was calculated as the mean of the media-only controls and subtracted from each data point. Background correction values ​​were calibrated by the corrected vehicle-treated controls (equivalent to 100% viability). GraphPad Data were analyzed using GraphPad Software, version 9.0.1 (GraphPad Software, Inc., La Jolla, CA / USA) to calculate the best-fit curve and EC 50 value (equivalent to the concentration of compound that achieves half (50%) of the maximal effect; lower EC 50 Values ​​thus indicate greater efficacy).

[0167] 2.1.2 Matrix survival rate determination (data analysis)

[0168] For each matrix assay, data were normalized to vehicle-treated controls (<0.5% DMSO; upper left corner) to obtain relative residual viability percentage values ​​according to the following formula:

[0169] % relative residual viability = background corrected signal treated cells / background corrected signal vehicle control x 100

[0170] Then use GraphPad Residual viability percentage values ​​were analyzed using GraphPad Software, version 9.0.1 (GraphPad Software, Inc., La Jolla, CA / USA) to calculate the best-fit curve and EC values ​​of individual active agents. 50 value.

[0171] At this point, the affected fraction (Fa), also called the fractional action, is calculated using the following formula:

[0172] Fa = 1-(% relative residual survival rate / 100)

[0173] For the following conditions:

[0174] Cells treated with serial dilutions of selumetinib as a single active agent.

[0175] Cells treated with serial dilutions of adrenostat as a single active agent.

[0176] · Use the equivalent of EC 50 The ratio of values ​​for cells treated with adalastat and selumetinib at a fixed ratio (the relative residual viability % values ​​on the diagonal of the matrix assay; Figure 1 and 2 ).

[0177] CalcuSyn software (http: / / www.biosoft.com / w / calcusyn.htm, Biosoft, Cambridge, UK) is designed to determine the nature of the interaction between two compounds (synergistic, additive or antagonistic) by calculating the combination index (CI). The analysis is based on the median action principle and the combination index theorem described in the Chou-Talalay method (Chou TC, Pharmacol Rev, 2006, 58 (3): 621-681, doi: 10.1124 / pr.58.3.10), wherein the obtained CI <1 indicates synergistic effect, CI = 1 indicates additive effect, and CI > 1 reflects antagonistic effect. In the case of synergistic effect (CI < 1), the smaller the CI value, the stronger the synergistic effect. In addition, the intensity of drug interactions can be further classified based on the CI range, as shown in Table 5.

[0178]

[0179] Table 5: Classification of drug interaction intensity based on CI. (Chou TC, Pharmacol Rev, 2006, 58(3): 621-681, doi: 10.1124 / pr.58.3.10)

[0180] In order to generate informative and consistent results, data processed using CalcuSyn (for both single active agents and drug combinations) need to conform to the median action principle and the combination index theorem theoretical model. Therefore, it is crucial to remove possible outliers and data points characterized by poor fit to the median action principle (Chou TC, Pharmacol Rev, 2006, 58 (3): 621-681, doi: 10.1124 / pr.58.3.10). To achieve this, the following strategy was used for data filtering:

[0181] In the first step, the data dispersion is reduced by removing points with the following characteristics:

[0182] 1)Fa<0.1

[0183] 2) Compared to the previous point (if Fa>0.9), Fa increases by <0.03.

[0184] These conditions define the plateau of the dose-response line, where treatment of cells with very low or very high concentrations of compound (or combination) results in a decrease in viability close to 0% or 100% (corresponding to Fa values ​​close to 0 or 1, respectively). Notably, in these regions of the dose-response curve, alamarBlue TMOr the changes in the MTT signal are very small and are most likely due to random noise and have little biological significance.

[0185] Next, for each data point, calculate Log 10 (Concentration) and Log 10 (Fa / (1-Fa)), and a dot plot was generated reporting the former value on the x-axis and the latter value on the y-axis. A regression line (equivalent to the median action equation) was then obtained using Excel.

[0186] At this point, the distance of each data point from the regression line is calculated using the following equation:

[0187] Distance (ax+by+c=0;X,Y)=(aX+bY+c) / √(a 2 +b 2 )

[0188] Outliers were identified using the Grubbs test based on their distance from the median action equation. For each data point, the absolute value of the distance was subjected to a Grubbs test according to the following formula (note that the variant of the Grubbs test can be referred to interchangeably as G or Z):

[0189] G=(X n -X 平均值 ) / s

[0190] Where X n represents the absolute value of the distance between each point and the regression line; X 平均值 Represents all X n The mean of the values, and s represents the standard deviation. crit The above G values ​​(calculated with α=0.2 as shown below) identified outliers that did not fit the median effect equation. Such data points were removed in order to successfully calculate the combination index using CalcuSyn.

[0191]

[0192] Where possible, repeat the test more than once to eliminate multiple outliers until:

[0193] 1. No other abnormal values ​​were found, or

[0194] 2.R 2 >0.95. To measure data quality, CalcuSyn software also calculated the R value (good data are characterized by R values ​​above 0.95).

[0195] 2.1.3 CalcuSyn Output

[0196] CalcuSyn results are provided as an experimental fractional action (called Fa), which represents the 50 The fraction of cells affected by the combined treatment at the ratio (in the case of cytotoxic treatments, the fractional effect is equivalent to a reduction in viability compared to the vehicle control, where Fa = 1 is equal to a 100% reduction in viability), and is provided as the associated combination index (CI). As shown in Table 5 above, the CI value indicates the nature and strength of the compound interaction, where values ​​below 1 indicate synergistic interactions (the closer the value is to 0, the stronger the synergy), values ​​equal to 1 indicate additive interactions, and values ​​above 1 indicate antagonistic interactions. The software also provides simulations of CI and Fa based on experimental data, and provides estimated CIs at ED75 and ED90 (effective doses corresponding to 75% and 90% reduction in survival, respectively), because for anticancer or antiviral agents, synergy at high action levels (e.g., at Fa>0.75) is more therapeutically relevant than low action levels (e.g., at Fa<0.2), as described in Chou TC, Cancer Res (2010) 70(2):440-446., doi:10.1158 / 0008-5472.CAN-09-1947.

[0197] Data presented include both the assay CIs for the associated Fa for each assay and the CIs estimated from the mean of ED75 and ED90 values ​​from 2 independent biological replicates.

[0198] 2.2 Results

[0199] As described in Section 2.1.1, matrix processing was performed using the MEK inhibitor selumetinib and the covalent and irreversible LSD1 inhibitor adrenaline. Data analysis and combination index calculation were performed as described in Section 2.1.2. Tables 6 and 7 show the results of the combination index (CI) associated with the specific fractional effect (Fa) obtained from the combination of adrenaline and selumetinib, the CI estimated at ED75 and ED90, and the corresponding classification (as described in Table 5).

[0200] In summary, the combination of adrenaline + selumetinib showed strong synergy across a wide range of fractional effects (Fa) in the three cell lines tested, including the patient-derived MPNST-NF1-18b cell line. Importantly, these synergistic effects were observed at biologically relevant effective doses (ED75 and ED90).

[0201]

[0202] Table 6: Test CI values ​​associated with corresponding Fa for the combination of Adasistat + Selumetinib and their classification. Results from two independent biological replicates are shown.

[0203]

[0204] Table 7: Estimated CI values ​​for ED75 and ED90 of the combination of Adalestinib and selumetinib and their classification. The average CI of two independent biological replicates is shown.

[0205] These results suggest that LSD1 inhibitors (eg, adrenaline) and MEK inhibitors (eg, selumetinib) interact in a synergistic manner across a diverse panel of MPNST cell lines, making the combination of these active agents particularly advantageous for the treatment of MPNST.

[0206] Example 3: Momentum for determining synergy between LSD1 inhibitors and Pi3K inhibitors in MPNST cell lines Array determination

[0207] 3.1 Experimental design

[0208] Matrix survival assays and corresponding analyses were performed as described in Example 2, but using the LSD1 inhibitor adrenaline and the Pi3K inhibitor cupanisib.

[0209] 3.2 Results

[0210] Matrix processing was performed using the Pi3K inhibitor cupanicib and the covalent and irreversible LSD1 inhibitor adrenaline as described in Section 2.1.1. Data analysis and combination index calculation were performed as described in Section 2.1.2. The results of the combination index (CI) associated with the specific fractional effect (Fa) obtained from the combination of adrenaline and cupanicib, the CI estimated at ED75 and ED90, and the corresponding classification (as described in Table 5) are shown in Tables 8 and 9.

[0211] In conclusion, the combination of adrenaline + cupranisib showed synergistic effects across a wide range of fractional effects (Fa). Importantly, these synergistic effects were observed at biologically relevant effective doses (ED75 and ED90).

[0212]

[0213] Table 8: Test CI values ​​associated with the corresponding Fa for the combination of Adalest + Cupanisib and their classification. Results from two independent biological replicates are shown.

[0214]

[0215] Table 9: Estimated CI values ​​for ED75 and ED90 of the combination of Adalest + Cupanisib and their classification. The average CI of two biological replicates is shown.

[0216] These results suggest that LSD1 inhibitors (such as adrenaline) and Pi3K inhibitors (such as cupranisib) interact in a synergistic manner in different MPNST cell lines, making the combination of such active agents particularly advantageous in the treatment of MPNST.

[0217] Although the invention has been described in conjunction with particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this patent or patent application is intended to cover any alternative embodiments, uses or improvements of the invention which generally follow the principles of the invention and include such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, and which departures from the basic characteristics described above and followed in the appended claims may be applicable.

Claims

1. An LSD1 inhibitor for use in the treatment of malignant peripheral nerve sheath tumors (MPNST).

2. A pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients, for use in treating malignant peripheral nerve sheath tumor (MPNST).

3. A method of treating malignant peripheral nerve sheath tumor (MPNST) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor.

4. Use of LSD1 inhibitors in the treatment of malignant peripheral nerve sheath tumors (MPNST).

5. Use of LSD1 inhibitors in the preparation of a pharmaceutical composition for treating malignant peripheral nerve sheath tumors (MPNST).

6. The LSD1 inhibitor for use according to claim 1, the pharmaceutical composition for use according to claim 2, the method according to claim 3, or the use according to claim 4 or 5, wherein the LSD1 inhibitor is a small molecule.

7. The LSD1 inhibitor for use according to claim 1 or 6, the pharmaceutical composition for use according to claim 2 or 6, the method of claim 3 or 6, or the use according to any one of claims 4 to 6, wherein the LSD1 inhibitor is selected from adrenaline, prodromalinostat, pomadelinestat, celidelinestat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile and pharmaceutically acceptable salts thereof.

8. The LSD1 inhibitor for use according to any one of claims 1, 6 or 7, the pharmaceutical composition for use according to any one of claims 2, 6 or 7, the method according to any one of claims 3, 6 or 7, or the use according to any one of claims 4-7, wherein the LSD1 inhibitor is selected from adrenaline, prolodiminostat, pomademostat and pharmaceutically acceptable salts thereof.

9. The LSD1 inhibitor for use according to any one of claims 1 or 6-8, the pharmaceutical composition for use according to any one of claims 2 or 6-8, the method according to any one of claims 3 or 6-8, or the use according to any one of claims 4-8, wherein the LSD1 inhibitor is adrenaline or a pharmaceutically acceptable salt thereof.

10. The LSD1 inhibitor for use according to claim 9, the pharmaceutical composition for use according to claim 9, the method according to claim 9, or the use according to claim 9, wherein the LSD1 inhibitor is adalestat dihydrochloride.

11. The LSD1 inhibitor for use according to any one of claims 1 or 6-8, the pharmaceutical composition for use according to any one of claims 2 or 6-8, the method according to any one of claims 3 or 6-8, or the use according to any one of claims 4-8, wherein the LSD1 inhibitor is prodromalar or a pharmaceutically acceptable salt thereof.

12. The LSD1 inhibitor for use according to claim 11, the pharmaceutical composition for use according to claim 11, the method according to claim 11, or the use according to claim 11, wherein the LSD1 inhibitor is prodromal stat besylate.

13. The LSD1 inhibitor for use according to any one of claims 1 or 6-8, the pharmaceutical composition for use according to any one of claims 2 or 6-8, the method according to any one of claims 3 or 6-8, or the use according to any one of claims 4-8, wherein the LSD1 inhibitor is pomadestat or a pharmaceutically acceptable salt thereof.

14. The LSD1 inhibitor for use according to claim 13, the pharmaceutical composition for use according to claim 13, the method according to claim 13, or the use according to claim 13, wherein the LSD1 inhibitor is pomadestat bis-tosylate.

15. The LSD1 inhibitor for use according to any one of claims 1 or 6-14, the pharmaceutical composition for use according to any one of claims 2 or 6-14, the method according to any one of claims 3 or 6-14, or the use according to any one of claims 4-14, wherein the MPNST is neurofibromatosis type I-associated MPNST, sporadic MPNST, or radiation-induced MPNST.

16. The LSD1 inhibitor for use according to any one of claims 1 or 6-14, the pharmaceutical composition for use according to any one of claims 2 or 6-14, the method according to any one of claims 3 or 6-14, or the use according to any one of claims 4-14, wherein the LSD1 inhibitor or the pharmaceutical composition is administered to an individual with neurofibromatosis type I.

17. The LSD1 inhibitor for use according to any one of claims 1 or 6-14, the pharmaceutical composition for use according to any one of claims 2 or 6-14, the method according to any one of claims 3 or 6-14, or the use according to any one of claims 4-14, wherein the LSD1 inhibitor or the pharmaceutical composition is administered to an individual who does not have neurofibromatosis type I.

18. The LSD1 inhibitor for use of any one of claims 1 or 6-17, the pharmaceutical composition for use of any one of claims 2 or 6-17, the method of any one of claims 3 or 6-17, or the use of any one of claims 4-17, wherein the MPNST has one or more mutations or genetic alterations affecting the NF1 gene.

19. The LSD1 inhibitor for use of any one of claims 1 or 6-18, the pharmaceutical composition for use of any one of claims 2 or 6-18, the method of any one of claims 3 or 6-18, or the use of any one of claims 4-18, wherein the MPNST has one or more mutations or genetic alterations affecting the expression and / or activity of CDKN2A, p53, RB1, PTEN, PRC2, EGFR, PDGFRA and / or c-Met.

20. The LSD1 inhibitor for use according to any one of claims 1 or 6-19, the pharmaceutical composition for use according to any one of claims 2 or 6-19, the method according to any one of claims 3 or 6-19, or the use according to any one of claims 4-19, wherein the MPNST is a metastatic MPNST.

21. The LSD1 inhibitor for use according to any one of claims 1 or 6-20, the pharmaceutical composition for use according to any one of claims 2 or 6-20, the method according to any one of claims 3 or 6-20, or the use according to any one of claims 4-20, wherein the LSD1 inhibitor or pharmaceutical composition is administered to an individual who is a human.

22. The LSD1 inhibitor for use according to any one of claims 1 or 6-21, the pharmaceutical composition for use according to any one of claims 2 or 6-21, the method according to any one of claims 3 or 6-21, or the use according to any one of claims 4-21, wherein the LSD1 inhibitor or the pharmaceutical composition is administered orally.

23. The LSD1 inhibitor for use according to any one of claims 1 or 6-22, the pharmaceutical composition for use according to any one of claims 2 or 6-22, the method according to any one of claims 3 or 6-22, or the use according to any one of claims 4-22, wherein the LSD1 inhibitor or the pharmaceutical composition is administered in combination with one or more additional anti-cancer agents and / or with radiotherapy.

24. A product comprising a LSD1 inhibitor and one or more additional anticancer agents in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in the treatment of malignant peripheral nerve sheath tumors (MPNST).

25. A method of treating malignant peripheral nerve sheath tumor (MPNST) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a preparation comprising a LSD1 inhibitor and one or more additional anti-cancer agents in the same pharmaceutical formulation or in separate pharmaceutical formulations.

26. The article for use of claim 24, or the method of claim 25, wherein: - a LSD1 inhibitor as defined in any one of claims 6 to 14; and / or - MPNST as defined in any one of claims 15 or 18-20; and / or - a subject to which the preparation is administered as defined in any one of claims 16, 17 or 21; and / or - The preparation is administered orally.

27. The article of manufacture for use of claim 24 or 26, or the method of claim 25 or 26, wherein the one or more additional anti-cancer agents comprises a MEK inhibitor.

28. The LSD1 inhibitor for use according to any one of claims 1 or 6-23, the pharmaceutical composition for use according to any one of claims 2 or 6-23, the method according to any one of claims 3 or 6-23, or the use according to any one of claims 4-23, wherein the LSD1 inhibitor or the pharmaceutical composition is administered in combination with a MEK inhibitor.

29. The LSD1 inhibitor for use according to claim 28, the pharmaceutical composition for use according to claim 28, the preparation for use according to claim 27, the method of claim 27 or 28, or the use of claim 28, wherein the MEK inhibitor is selected from selumetinib, trametinib, cobimetinib, bimetinib, midametinib, pimatitinib, rifatinib, zanotinib, ivometinib, HL-085, FCN-159, TAK-733 and pharmaceutically acceptable salts thereof.

30. The LSD1 inhibitor for use according to claim 28, the pharmaceutical composition for use according to claim 28, the preparation for use according to claim 27, the method of claim 27 or 28, or the use of claim 28, wherein the MEK inhibitor is selumetinib or a pharmaceutically acceptable salt thereof, and the LSD1 inhibitor is adrenaline or a pharmaceutically acceptable salt thereof.

31. The article of manufacture for use of claim 24 or 26, or the method of claim 25 or 26, wherein the one or more additional anti-cancer agents comprises a Pi3K inhibitor.

32. The LSD1 inhibitor for use according to any one of claims 1 or 6-23, the pharmaceutical composition for use according to any one of claims 2 or 6-23, the method according to any one of claims 3 or 6-23, or the use according to any one of claims 4-23, wherein the LSD1 inhibitor or the pharmaceutical composition is administered in combination with a Pi3K inhibitor.

33. The LSD1 inhibitor for use according to claim 32, the pharmaceutical composition for use according to claim 32, the preparation for use according to claim 31, the method of claim 31 or 32, or the use of claim 32, wherein the Pi3K inhibitor is selected from cupanisib, apellisib, idelalisib, duvilisib, erbulisib, bupalisib, zanalisib, limplisib, pazalisib, lanilisib, pazalisib, inarlisib, celabelisib, pitilisib, tacelisib, tenalisib, egalisib, GSK2636771, MEN1611, AMG-319 and pharmaceutically acceptable salts thereof.

34. The LSD1 inhibitor for use according to claim 32, the pharmaceutical composition for use according to claim 32, the preparation for use according to claim 31, the method of claim 31 or 32, or the use of claim 32, wherein the Pi3K inhibitor is kupanisib or a pharmaceutically acceptable salt thereof, and the LSD1 inhibitor is adrenaline or a pharmaceutically acceptable salt thereof.

Images