Methods of treating nf1-mutant tumors using LSD1 inhibitors

Abstract

The present invention relates to LSD1 inhibitors for use in the treatment of NF1-mutant tumors, i.e. Tumors having one or more mutations or genetic alterations that affect the NF1 gene. The invention also provides a method of treating an NF1-mutant tumor 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 NF1-mutant tumors, i.e. tumors having one or more mutations or genetic alterations affecting the NF1 gene. In particular, the present invention provides LSD1 inhibitors for use in treating NF1-mutant tumors. The present invention also provides a method of treating NF1-mutant tumors in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a LSD1 inhibitor.

[0003] background

[0004] Tumors, especially malignant tumors (cancer), are one of the leading causes of death worldwide. The clinical treatment of cancer has changed fundamentally in 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 mechanisms. Today, new personalized and precision medicine approaches are designed to block the growth of cancer cells while mainly protecting 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] NF1 is a tumor suppressor gene mutated in neurofibromatosis type I, one of the most common monogenic disorders, affecting approximately 1 in 3,000 people. This is an autosomal dominant syndrome characterized by a susceptibility to the development of benign tumors called plexiform neurofibromas (PNs), which may eventually become malignant (malignant peripheral nerve sheath tumors - MPNSTs) and are accompanied by a range of neurodevelopmental problems, such as cognitive and learning disabilities, epilepsy, speech problems, autism, and hyperactivity. Neurofibromatosis patients are also prone to a range of malignancies other than MPNSTs, such as gliomas, gastrointestinal stromal tumors, rhabdomyosarcomas, and leukemias. The NF1 gene, like many other tumor suppressor genes such as p53, PTEN, or Rb, is also frequently mutated in a variety of non-neurofibromatosis-related cancers. Thus, it has been described that somatic mutations of the NF1 gene occur at frequencies as high as 12-30% in cutaneous melanoma, 3.5-23.6% in acute myeloid leukemia, 12-34.4% in ovarian cancer, 14-23% in glioblastoma, and 10.3-11% in squamous cell carcinoma of the lung, etc. (Philpott C et al., Hum Genomics, 2017, 11(1):13, doi:10.1186 / s40246-017-0109-3). Therefore, mutations in the NF1 gene promote the occurrence of a variety of malignant tumors with and without neurofibromatosis type I. The NF1 gene protein product, neurofibromin, is a negative regulator of the RAS pathway, a signaling axis that promotes cell growth and division. A well-established assumption is that germline or somatic mutations in the NF1 gene promote cancer progression by impairing the negative control of RAS by neurofibromin (Philpott C et al., loc.cit.; Tao J et al., Cancer Cell Int, 2020, 20:492, doi:10.1186 / s12935-020-01570-8). However, NF1 is a huge gene consisting of approximately 60 exons, which encodes a large multi-domain protein consisting of more than 2800 amino acids. Therefore, it may have many functions other than RAS inhibition, which may also be related to tumorigenesis. Many malignant tumors driven in part by NF1 gene mutations have very poor prognosis and still require targeted therapy. Therefore, the development of new therapeutic options to treat NF1-mutated tumors has significant pharmaceutical and medical significance. 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 prolodexstat, are advantageously effective in treating NF1-mutated tumors, particularly including NF1-mutated acute myeloid leukemia (AML), NF1-mutated acute lymphoblastic leukemia (ALL), NF1-mutated malignant rhabdoid tumor (MRT), NF1-mutated small cell lung cancer (SCLC), NF1-mutated malignant peripheral nerve sheath tumor (MPNST) and NF1-mutated plexiform neurofibroma, as also further described in the Examples section below. Thus, the present invention provides particularly advantageous and targeted therapeutic methods for treating NF1-mutated tumors.

[0009] Therefore, the present invention relates to LSD1 inhibitors for use in treating NF1-mutant tumors.

[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 NF1-mutant tumors.

[0011] The present invention also provides a method of treating an NF1-mutant tumor 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] Additionally, the present invention relates to the use of LSD1 inhibitors in the treatment of NF1-mutant tumors.

[0013] The present invention also relates to the use of LSD1 inhibitors in the preparation of a drug (or a pharmaceutical composition) for treating NF1-mutant tumors. DETAILED DESCRIPTION OF THE INVENTION

[0015] As described above, the present invention is based on the surprising discovery that LSD1 inhibitors are advantageously effective in treating NF1-mutated tumors, particularly including NF1-mutated acute myeloid leukemia (AML), NF1-mutated acute lymphoblastic leukemia (ALL), NF1-mutated malignant rhabdoid tumor (MRT), NF1-mutated small cell lung cancer (SCLC), NF1-mutated malignant peripheral nerve sheath tumor (MPNST) and NF1-mutated plexiform neurofibroma, as also further described and demonstrated in the Examples section below. Thus, the exemplary LSD1 inhibitor adrenaline was found to be highly effective in a range of different NF1-mutated tumor cell lines. It was also demonstrated that other LSD1 inhibitors having different chemical backbones and including reversible and irreversible LSD1 inhibitors can effectively treat NF1-mutated tumors, as also described in the Examples section.

[0016] Therefore, the present invention relates to LSD1 inhibitors for treating NF1-mutant tumors. The present invention also relates to a pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients, which is used to treat NF1-mutant tumors. The present invention also provides a method for treating NF1-mutant tumors 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 LSD1 inhibitors in treating NF1-mutant tumors. The present invention also relates to the use of LSD1 inhibitors in the preparation of a medicament (or pharmaceutical composition) for treating NF1-mutant tumors.

[0017] 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).

[0018] 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.

[0019] 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.

[0020] The NF1-mutant tumor treated according to the present invention may be any tumor (including, for example, any of the special types of tumors listed further below) having one or more mutations or genetic changes affecting the NF1 gene (for example, any one or more of the special mutations / genetic changes mentioned or referred to below), in particular one or more inactivating mutations or inactivating genetic changes affecting the NF1 gene. Therefore, the present invention particularly relates to the treatment of NF1-mutant tumors having one or more inactivating mutations or inactivating genetic changes in the NF1 gene. Such inactivating mutations or inactivating genetic changes affecting 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.

[0021] The NF1-mutated tumors treated according to the present invention may be malignant (cancerous) or benign (non-cancerous). In addition, the malignant or benign NF1-mutated tumors may be solid tumors or non-solid tumors. Preferably, the NF1-mutated tumor is a NF1-mutated malignant tumor, i.e., a NF1-mutated cancer.

[0022] Examples of NF1-mutated malignancies (or NF1-mutated cancers) treated according to the present invention include, in particular, NF1-mutated leukemias (e.g., NF1-mutated acute myeloid leukemia (AML), NF1-mutated acute lymphoblastic leukemia (ALL) or NF1-mutated T-cell acute lymphoblastic leukemia), NF1-mutated lymphomas (e.g., NF1-mutated non-Hodgkin's lymphoma, also including NF1-mutated Burkitt's lymphoma), NF1-mutated lung cancers (e.g., NF1-mutated small cell lung cancer (SCLC) or NF1-mutated non-small cell lung cancer (NSCLC), also including NF1-mutated squamous cell carcinoma of the lung), NF1-mutated breast cancers (e.g., NF1-mutated triple-negative breast cancer), NF1-mutated esophagogastric cancer, NF1-mutated esophageal cancer, NF1-mutated gastric cancer, NF1-mutated gastrointestinal cancer, NF1-mutated colorectal cancer (e.g., NF1-mutated carcinoma), NF1-mutated liver cancer, NF1-mutated ovarian cancer, NF1-mutated pancreatic cancer, NF1-mutated pancreatic cancer, NF1-mutated ovarian cancer, NF1-mutated esophageal cancer, NF1-mutated gastric cancer, NF1-mutated gastrointestinal cancer, NF1-mutated colorectal cancer (cancer) (e.g., NF1-mutated colorectal cancer (carcinoma)), NF1-mutated NF1-mutated uterine cancer (e.g., NF1-mutated carcinoma), NF1-mutated cervical cancer (e.g., NF1-mutated cervical cancer (carcinoma)), NF1-mutated pancreatic cancer, NF1-mutated prostate cancer (e.g., NF1-mutated prostate adenocarcinoma), NF1-mutated bladder cancer (e.g., NF1-mutated bladder cancer (carcinoma)), NF1-mutated pheochromocytoma, NF1-mutated head and neck cancer (e.g., NF1-mutated head and neck cancer (carcinoma)), NF1-mutated neuroblastoma, NF1-mutated glioblastoma, NF1-mutated optic pathway glioma, NF1-mutated skin cancer (e.g., NF1-mutated melanoma, also including NF1-mutated desmoplastic melanoma), NF1-mutated malignant rhabdoid tumor, NF1-mutated rhabdomyosarcoma, NF1-mutated Ewing's sarcoma, or NF1-mutated malignant peripheral nerve sheath tumor (MPNST).

[0023] As mentioned above, although the NF1-mutated tumors to be treated are preferably NF1-mutated malignant tumors, the present invention also particularly relates to NF1-mutated benign tumors (and may also be referred to as NF1-mutated benign neoplastic disorders) which also constitute pathological conditions. Examples of NF1-mutated benign tumors particularly include NF1-mutated plexiform neurofibromas, NF1-mutated ganglioneuromas, NF1-mutated iridochromomas or NF1-mutated cutaneous neurofibromas. NF1-mutated benign tumors may also be NF1-mutated premalignant tumors.

[0024] Particularly preferred examples of NF1-mutated tumors treated according to the present invention include NF1-mutated leukemia (e.g. NF1-mutated AML or NF1-mutated ALL), NF1-mutated malignant rhabdoid tumor, NF1-mutated lung cancer (e.g. NF1-mutated SCLC), NF1-mutated MPNST or NF1-mutated plexiform neurofibroma.

[0025] Furthermore, the NF1-mutated tumor to be treated may also be a NF1-mutated tumor that is not a NF1-mutated MPNST (including the above-mentioned special types of malignant or benign NF1-mutated tumors that are different from MPNSTs).

[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.

[0027] 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.

[0028] The domain structure of neurofibromin is complex and contains, from N-terminus to C-terminus:

[0029] (1) N-thermal domain, which contains a cysteine- and serine-rich domain / GTPase activation domain (CSRD) and a tubulin-binding domain (TBD);

[0030] (2) GTPase-activation domain (GAP)-related domain (GRD), which promotes the hydrolysis of active Ras-GTP to the inactive form Ras-GDP;

[0031] (3) Sec14 homologous fragment;

[0032] (4) pleckstrin homology (PH)-like domain; and

[0033] (5) The C-HEAT domain comprises a HEAT-like repeat domain (HLR) and a C-terminal domain (CTD), in which the syndecan-binding domain (SBD) is found.

[0034] Furthermore, the Sec14, PH-like and HLR domains constitute components of the so-called leucine-rich domain (LRD). Dimerization sites are found scattered within the N-hot domain (at the distal N-terminus and TBD) and particularly in the C-hot domain.

[0035] Typically, the NF1-mutant tumors 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 (or several) of the above-mentioned domains or fragments of the NF1 gene product neurofibromin.

[0036] Thus, for example, a NF1-mutant tumor can be a NF1-mutant tumor (eg, NF1-mutant AML) having one or more inactivating mutations located in the GTPase activation domain (GAD)-related domain (GRD) of NF1.

[0037] In some embodiments, NF1-mutant tumors have one or more inactivating mutations located in the cysteine ​​and serine rich domain / GTPase activation domain (CSRD) of NF1.

[0038] In some embodiments, NF1-mutant tumors have one or more inactivating mutations located in the leucine-rich domain (LRD) of NF1.

[0039] In some embodiments, the NF1-mutant tumor has one or more inactivating mutations located on at least one dimerization interface of NF1.

[0040] Furthermore, the present invention particularly relates to treating an NF1-mutant tumor in an individual, the individual having been determined (or diagnosed) to suffer from an NF1-mutant tumor (e.g. any of the above-mentioned particular or exemplary NF1-mutant tumors). In particular, the present invention also relates to a corresponding treatment (or a corresponding method or use), comprising the step of testing an individual for the presence of a tumor having one or more mutations or genetic alterations affecting the NF1 gene (including, for example, any of the above-mentioned mutations or genetic alterations), and, if the presence of such mutations or genetic alterations has been determined, comprising the subsequent step of administering to the individual an LSD1 inhibitor.

[0041] Therefore, the present invention provides LSD1 inhibitors for use in treating NF1-mutated tumors in individuals who have been determined (or diagnosed) to have NF1-mutated tumors. The present invention also relates to pharmaceutical compositions comprising LSD1 inhibitors and optionally one or more pharmaceutically acceptable excipients for use in treating NF1-mutated tumors in individuals who have been determined (or diagnosed) to have NF1-mutated tumors. The present invention also provides methods for treating NF1-mutated tumors in individuals who have been determined (or diagnosed) to have NF1-mutated tumors, the methods comprising administering to an individual in need thereof 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 LSD1 inhibitors in treating NF1-mutated tumors in individuals who have been determined (or diagnosed) to have NF1-mutated tumors. The present invention also relates to the use of LSD1 inhibitors in the preparation of a medicament (or pharmaceutical composition) for treating NF1-mutated tumors in individuals who have been determined (or diagnosed) to have NF1-mutated tumors.

[0042] In addition, the present invention provides LSD1 inhibitors for use in treating NF1-mutant tumors, wherein the use comprises the step of testing an individual for the presence of a tumor with one or more mutations or genetic changes affecting the NF1 gene (including, for example, any of the above mutations or genetic changes), and if the presence of the mutation or genetic change affecting the NF1 gene has been determined, then the step of administering the LSD1 inhibitor to the individual is included. The present invention also relates to a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients, which is used to treat NF1-mutant tumors, wherein the use comprises the step of testing an individual for the presence of a tumor with one or more mutations or genetic changes affecting the NF1 gene (including, for example, any of the above mutations or genetic changes), and if the presence of the mutation or genetic change affecting the NF1 gene has been determined, then the step of administering the pharmaceutical composition to the individual is included. The present invention also provides a method for treating NF1-mutant tumors in an individual in need thereof, the method comprising the step of testing the individual for the presence of a tumor with one or more mutations or genetic alterations affecting the NF1 gene (including, for example, any of the mutations or genetic alterations described above), and if the presence of the mutations or genetic alterations affecting the NF1 gene has been determined, then the step of 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 LSD1 inhibitors in the treatment of NF1-mutant tumors, wherein the treatment comprises testing the individual for the presence of a tumor with one or more mutations or genetic alterations affecting the NF1 gene (including, for example, any of the mutations or genetic alterations described above), and if the presence of the mutations or genetic alterations affecting the NF1 gene has been determined, then the step of administering to the individual a LSD1 inhibitor. The present invention also relates to the use of an LSD1 inhibitor in the preparation of a medicament (or a pharmaceutical composition) for treating an NF1-mutant tumor, wherein the treatment comprises testing an individual for a tumor having one or more mutations or genetic changes affecting the NF1 gene (including, for example, any of the mutations or genetic changes mentioned above), and administering the medicament (or the pharmaceutical composition) to the individual if the presence of the mutation or genetic change affecting the NF1 gene has been determined.

[0043] Although mutations or genetic changes in the NF1 gene are hallmarks of neurofibromatosis type I, a genetic disease, such mutations or genetic changes contribute to the development of a range of different tumors in individuals with neurofibromatosis type I and in individuals who do not have neurofibromatosis type I. Therefore, in some embodiments, the present invention relates to treating NF1-mutated tumors in individuals with neurofibromatosis type I. Therefore, the present invention relates to LSD1 inhibitors (or pharmaceutical compositions comprising LSD1 inhibitors) for use in treating NF1-mutated tumors, wherein the LSD1 inhibitors (or pharmaceutical compositions) are administered to individuals with neurofibromatosis type I. The present invention also particularly relates to treating NF1-mutated tumors in individuals who do not have neurofibromatosis type I. Therefore, in some embodiments, the present invention relates to LSD1 inhibitors (or pharmaceutical compositions comprising LSD1 inhibitors) for use in treating NF1-mutated tumors, wherein the LSD1 inhibitors (or pharmaceutical compositions) are administered to individuals who do not have neurofibromatosis type I.

[0044] The NF1-mutant tumor treated may also be a metastatic NF1-mutant malignancy, i.e. a metastatic NF1-mutant cancer. Thus, the NF1-mutant tumor treated may be a primary NF1-mutant cancer that has formed metastases, i.e. has spread to one or more other sites in the individual's body.

[0045] The NF1-mutant tumor treated may also be a relapsed or refractory NF1-mutant cancer.

[0046] The therapeutic effect of LSD1 inhibitors in treating NF1-mutant tumors can be further confirmed in additional in vitro or in vivo assays as well as human clinical trials, which can be easily established by one of ordinary skill in the art of drug development.

[0047] LSD1 inhibitors

[0048] 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 the Examples section below, according to the present invention, both irreversible and reversible LSD-1 inhibitors can be used to treat NF1-mutated tumors. Typical irreversible LSD1 inhibitors include cyclopropylamine-based compounds, such as adrenaline and pomadestat, which belong to the LSD1 inhibitors used in the Examples section. A representative example of a reversible LSD1 inhibitor is the compound prolodrumstat, which is also used in the Examples section. 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).

[0049] An exemplary list of small molecule LSD1 inhibitors is provided in the table below:

[0050]

[0051]

[0052] 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.

[0053] 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. ,

[0054] 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).

[0055] Adalestad is a selective and irreversible LSD1 inhibitor. Adalestad is the INN of the compound of the following formula:

[0056]

[0057] [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.

[0058] Prodromostat is a reversible LSD1 inhibitor of the formula

[0059]

[0060] [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.

[0061] Pomidostat is an irreversible LSD1 inhibitor of the formula

[0062]

[0063] [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.

[0064] Celidenostat is a LSD1 inhibitor of the formula

[0065]

[0066] [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.

[0067] 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:

[0068]

[0069] 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:

[0070]

[0071] Vafidostat is an irreversible LSD1 inhibitor of the following formula:

[0072]

[0073] 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.

[0074] 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:

[0075]

[0076] Other examples of LSD1 inhibitors include SYHA1807 or a pharmaceutically acceptable salt thereof or JBI-802 or a pharmaceutically acceptable salt thereof.

[0077] 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.

[0078] 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.

[0079] 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).

[0080] 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).

[0081] 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.

[0082] Pharmaceutical preparations

[0083] 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.

[0084] 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.

[0085] 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).

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] Suitable oral dosage forms of adrenaline are disclosed, for example, in WO2019 / 211491.

[0092] 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.

[0093] For the treatment of NF1-mutant tumors, 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.

[0094] 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.

[0095] 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.

[0096] 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).

[0097] 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.

[0098] Combination therapy

[0099] 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). Therefore, 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 NF1-mutant tumors (preferably NF1-mutant cancers). The present invention also relates to corresponding methods and uses for monotherapy treatment of NF1-mutant tumors (preferably NF1-mutant cancers).

[0100] 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.

[0101] 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.

[0102] 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).

[0103] Therefore, the present invention relates to LSD1 inhibitors for use in combination with one or more additional therapeutic agents (particularly one or more additional anticancer agents) and / or in combination with radiotherapy for the treatment of NF1-mutant tumors (preferably NF1-mutant cancers). The present invention also relates to pharmaceutical compositions comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients for use in combination with one or more additional therapeutic agents (particularly one or more additional anticancer agents) and / or in combination with radiotherapy for the treatment of NF1-mutant tumors (preferably NF1-mutant cancers). The present invention also relates to LSD1 inhibitors (or pharmaceutical compositions comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients) for use in the treatment of NF1-mutant tumors (preferably NF1-mutant cancers), wherein the LSD1 inhibitor (or pharmaceutical composition comprising an LSD1 inhibitor) is administered 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 an LSD1 inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients) for use in treating NF1-mutated tumors (preferably NF1-mutated cancers), wherein the LSD1 inhibitor (or a pharmaceutical composition comprising an 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 treating NF1-mutated tumors (preferably NF1-mutated cancers) in combination with an LSD1 inhibitor; (ii) an anticancer agent for treating NF1-mutated tumors (preferably NF1-mutated cancers), wherein the anticancer agent is administered in combination with an LSD1 inhibitor; or (iii) an anticancer agent for treating NF1-mutated tumors (preferably NF1-mutated cancers), wherein the anticancer agent is applied in combination with an LSD1 inhibitor.

[0104] The present invention also provides a method for treating NF1-mutant tumors (preferably NF1-mutant cancers) 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.

[0105] In addition, the present invention relates to the use of LSD1 inhibitors in combination with one or more additional therapeutic agents (particularly one or more additional anticancer agents) and / or in combination with radiotherapy in the treatment of NF1-mutated tumors (preferably NF1-mutated cancers). The present invention also relates to the use of anticancer agents in combination with LSD1 inhibitors in the treatment of NF1-mutated tumors (preferably NF1-mutated cancers).

[0106] The present invention also relates to the use of LSD1 inhibitors in combination with one or more additional therapeutic agents (particularly 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 NF1-mutated tumors (preferably NF1-mutated cancers). The present invention also relates to the use of an anticancer agent in combination with an LSD1 inhibitor in the preparation of a medicament for the treatment of NF1-mutated tumors (preferably NF1-mutated cancers). The present invention also relates to the use of an LSD1 inhibitor and one or more additional anticancer agents in the preparation of a medicament for the treatment of NF1-mutated tumors (preferably NF1-mutated cancers), wherein the medicament comprises the LSD1 inhibitor and the additional anticancer agent in the same pharmaceutical formulation or in separate pharmaceutical formulations. The present invention also relates to the use of an LSD1 inhibitor in the preparation of a medicament for the treatment of NF1-mutated tumors (preferably NF1-mutated cancers), wherein the medicament is prepared for application (or for combined application) in combination with one or more additional therapeutic agents (particularly 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 treating NF1-mutant tumors (preferably NF1-mutant cancers), wherein the medicament is prepared for combined use (or for combined use) with a LSD1 inhibitor.

[0107] 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 treating NF1-mutant tumors (preferably NF1-mutant cancers). 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.

[0108] 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 treating NF1-mutant tumors (preferably NF1-mutant cancers).

[0109] 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 anticancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in treating NF1-mutant tumors (preferably NF1-mutant cancers).

[0110] The present invention also provides a method for treating NF1-mutated tumors (preferably NF1-mutated cancers) 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 NF1-mutated tumors (preferably NF1-mutated cancers) 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 (especially 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 NF1-mutated tumors (preferably NF1-mutated cancers) 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 (especially one or more additional anticancer agents).

[0111] 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 treating NF1-mutated tumors (preferably NF1-mutated cancers). 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 NF1-mutated tumors (preferably NF1-mutated cancers).

[0112] 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).

[0113] 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.

[0114] As described above, the one or more additional therapeutic agents used in combination with the LSD1 inhibitor of the present 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 NF1-mutant tumors (preferably NF1-mutant cancers) 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 LSD1 inhibitors, one or more additional anticancer agents and an antiemetic. The antiemetic can 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, lerisetron, licarsetron or zaltosetron; olanzapine; a corticosteroid, such as methylprednisone or dexamethasone; or prochlorperazine.

[0115] Products

[0116] A pharmaceutical composition (or formulation) of the invention may be included in a container, pack, or dispenser together with instructions for administration.

[0117] Thus, in another embodiment, the present invention provides an article of manufacture comprising a LSD1 inhibitor or a pharmaceutical composition comprising a LSD1 inhibitor for use in treating a NF1 -mutant tumor as described herein.

[0118] In some embodiments, an article of manufacture comprises a container and a pharmaceutical composition as described herein for use of the invention.

[0119] In some embodiments, the present invention provides an article of manufacture (or kit) comprising a container and a combination product (as described above) for treating NF1-mutated tumors (particularly NF1-mutated cancers). The present invention also provides an article of manufacture (or kit) comprising: (i) a first container comprising an LSD1 inhibitor, (ii) a second container comprising another anticancer agent (as described above), and (iii) one or more additional containers optionally comprising one or more additional anticancer agents, for treating NF1-mutated tumors (particularly NF1-mutated cancers).

[0120] 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 the use of 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 NF1-mutant tumors. Optionally 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] definition

[0126] 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.

[0127] The following definitions apply throughout the specification and claims, unless specifically stated otherwise.

[0128] 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.

[0129] 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 (e.g., an NF1-mutant tumor) 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 (e.g., an NF1-mutant tumor), including but not limited to inhibiting the disease, i.e., arresting, delaying or slowing its development / progression; or alleviating the disease, i.e., causing its (complete or partial) regression, alleviation, correction or slowing. The present invention particularly and explicitly relates to each of these forms of treatment.

[0130] 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 (e.g., an NF1-mutant tumor) 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.

[0131] 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.

[0132] 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).

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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).

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Example

[0143] 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.

[0144] Example 1: Effects of LSD1 inhibitors on NF1-mutant tumor cell lines

[0145] Experimental Design

[0146] Mycoplasma-free tumor cell lines from different tumor types carrying mutations in the NF1 gene (see Table 1) were seeded in 50 μL / well of complete medium (as described in Table 2, all reagents from ThermoFisher) (in 96-well plates) at optimal cell density to ensure logarithmic growth throughout the experiment (see Table 2). The next day after seeding, 50 μL of medium containing 9 serial dilutions (1:3) of 2× concentrated adrenaline (LSD1 inhibitor; used as dihydrochloride) was added to the cells to obtain 100 μL of cells treated with 1× concentrated compound for each dilution. In addition, the effects of other LSD1 inhibitors, namely pomadestat (bis-tosylate) and prolodrestat (besylate), were also evaluated in subsets of these tumor cell lines (sNF96.2, sNF02.2, MOLM13, and NCIH510A).

[0147] Each experimental condition was tested in triplicate, including wells with medium only 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 (see Table 2 for treatment time according to the growth curve of each cell line and the number of cells seeded), and when the treatment time period exceeded 4 days of drug incubation, compound and medium renewal was performed by adding 50 μL of medium supplemented with 1× concentrated compound at each corresponding dilution (see Table 2). After treatment, MTT assay (Sigma-Aldrich) or AlamarBlue was used according to the manufacturer's instructions. TM Cell viability was assessed using the Cell Viability Reagent (Life Technologies). Background was calculated as the mean of the media-only control values ​​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).

[0148]

[0149] Table 1: Different tumor cell lines used and their corresponding NF1 mutations (SCLC: small cell lung cancer; MPNST: malignant peripheral nerve sheath tumor; ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; TN breast cancer: triple negative breast cancer; LOH: loss of heterozygosity; p.: mutation in protein sequence; c.: mutation in DNA sequence; SNP: single nucleotide polymorphism; SNV: single nucleotide variant; *: mutation in the 3' generating STOP codon; NS: not specified).

[0150]

[0151]

[0152] Table 2: Cell lines used for adrenaline treatment (FBS: fetal bovine serum) and their corresponding experimental conditions.

[0153] result

[0154] Fifteen NF1-mutant cell lines representing 10 different tumor types were used to evaluate the effect of the LSD1 inhibitor adrenostat on cell survival in a range of different NF1-mutant tumors.

[0155] 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 tumor 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 adrenaline 50 Values, and classification according to decreased survival after LSD1 inhibitor treatment.

[0156]

[0157] Table 3: Effect of the LSD1 inhibitor Adaristat on cell viability of the indicated NF1-mutant tumor cell lines.

[0158] As shown in Table 3, 9 of 15 tumor cell lines carrying NF1 mutations (60.0%) responded favorably to LSD1 inhibitor treatment. Of these 9 cell lines, 7 (46.7%) showed strong responses to the LSD1 inhibitor adrenaline, and 2 (13.3%) showed moderate responses. Notably, all 9 favorable responding cell lines showed subnanomolar EC values ​​for adrenaline. 50 values ​​(see Table 3), indicating that even at very low doses, it has a clinically relevant therapeutic effect.

[0159] The effects of LSD1 inhibitors on cell viability of NF1-mutant tumor cells were further tested using two other LSD1 inhibitors, namely, pomadestat and prolodrumostat. Pomadestat, such as adalrestat, is an irreversible LSD1 inhibitor, while prolodrumostat is a reversible LSD1 inhibitor. According to the above method, cell viability was evaluated in sNF96.2 (MPNST), sNF02.2 (MPNST), MOLM13 (AML) and NCIH510A (SCLC) cell lines (see Table 2). As shown in Table 4 (and for adalrestat, in Table 3 above), the results obtained thereby clearly show that all three LSD1 inhibitors are effective against NF1-mutant tumors, regardless of whether they are irreversible or reversible LSD1 inhibitors.

[0160]

[0161] Table 4: Effects of different LSD1 inhibitors on cell viability of indicative NF1 -mutant tumor cell lines.

[0162] Among the LSD1 inhibitors tested, adrenaline showed the highest efficacy (lowest EC 50 ).

[0163] These results suggest that LSD1 inhibitors, including irreversible LSD1 inhibitors (eg, adrenostat and pomadestat) and reversible LSD1 inhibitors (eg, prolostat) are advantageously effective in treating NF1-mutated tumors harboring both germline and somatic NF1 mutations.

[0164] 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. LSD1 inhibitors for use in the treatment of NF1-mutated tumors.

2. A pharmaceutical composition comprising a LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients, for use in treating NF1-mutant tumors.

3. A method of treating an NF1-mutant tumor 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 NF1-mutated tumors.

5. Use of LSD1 inhibitors in the preparation of pharmaceutical compositions for treating NF1-mutant tumors.

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 adalastat, prodromostat, pomadestat, celidestat, 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 NF1-mutant tumor is a NF1-mutant cancer.

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 NF1-mutant tumor is selected from the group consisting of NF1-mutant leukemia, NF1-mutant lymphoma, NF1-mutant lung cancer, NF1-mutant breast cancer, NF1-mutant esophagogastric cancer, NF1-mutant esophageal cancer, NF1-mutant gastric cancer, NF1-mutant gastrointestinal cancer, NF1-mutant colorectal cancer, NF1-mutant liver cancer, NF1-mutant ovarian cancer, NF1-mutant uterine cancer, NF1-mutated cervical cancer, NF1-mutated pancreatic cancer, NF1-mutated prostate cancer, NF1-mutated bladder cancer, NF1-mutated pheochromocytoma, NF1-mutated head and neck cancer, NF1-mutated neuroblastoma, NF1-mutated glioblastoma, NF1-mutated optic pathway glioma, NF1-mutated skin cancer, NF1-mutated malignant rhabdoid tumor, NF1-mutated rhabdomyosarcoma, NF1-mutated Ewing sarcoma, NF1-mutated malignant peripheral nerve sheath tumor, NF1-mutated plexiform neurofibroma, NF1-mutated ganglioneuroma, NF1-mutated iridochromocytoma, and NF1-mutated cutaneous neurofibroma.

17. The LSD1 inhibitor for use according to any one of claims 1 or 6-16, the pharmaceutical composition for use according to any one of claims 2 or 6-16, the method according to any one of claims 3 or 6-16 or the use according to any one of claims 4-16, wherein the NF1-mutant tumor is a NF1-mutant leukemia.

18. The LSD1 inhibitor for use according to claim 17, the pharmaceutical composition for use according to claim 17, the method according to claim 17 or the use according to claim 17, wherein the NF1-mutated leukemia is NF1-mutated acute myeloid leukemia or NF1-mutated acute lymphoblastic leukemia.

19. The LSD1 inhibitor for use according to any one of claims 1 or 6-16, the pharmaceutical composition for use according to any one of claims 2 or 6-16, the method according to any one of claims 3 or 6-16 or the use according to any one of claims 4-16, wherein the NF1-mutant tumor is a NF1-mutant lung cancer.

20. The LSD1 inhibitor for use according to claim 19, the pharmaceutical composition for use according to claim 19, the method according to claim 19 or the use according to claim 19, wherein the NF1-mutated lung cancer is a NF1-mutated small cell lung cancer.

21. The LSD1 inhibitor for use according to any one of claims 1 or 6-16, the pharmaceutical composition for use according to any one of claims 2 or 6-16, the method according to any one of claims 3 or 6-16 or the use according to any one of claims 4-16, wherein the NF1-mutant tumor is a NF1-mutant malignant rhabdoid tumor.

22. The LSD1 inhibitor for use according to any one of claims 1 or 6-16, the pharmaceutical composition for use according to any one of claims 2 or 6-16, the method according to any one of claims 3 or 6-16 or the use according to any one of claims 4-16, wherein the NF1-mutant tumor is a NF1-mutant malignant peripheral nerve sheath tumor.

23. 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 NF1-mutant tumor is a NF1-mutant plexiform neurofibroma.

24. 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 NF1-mutant tumor has one or more inactivating mutations or inactivating genetic alterations affecting the NF1 gene.

25. The LSD1 inhibitor for use according to any one of claims 1 or 6-24, the pharmaceutical composition for use according to any one of claims 2 or 6-24, the method according to any one of claims 3 or 6-24 or the use according to any one of claims 4-24, wherein the LSD1 inhibitor or the pharmaceutical composition is administered to an individual with neurofibromatosis type I.

26. The LSD1 inhibitor for use according to any one of claims 1 or 6-24, the pharmaceutical composition for use according to any one of claims 2 or 6-24, the method according to any one of claims 3 or 6-24 or the use according to any one of claims 4-24, wherein the LSD1 inhibitor or the pharmaceutical composition is administered to an individual who does not have neurofibromatosis type I.

27. The LSD1 inhibitor for use according to any one of claims 1 or 6-26, the pharmaceutical composition for use according to any one of claims 2 or 6-26, the method according to any one of claims 3 or 6-26 or the use according to any one of claims 4-26, wherein the LSD1 inhibitor or the pharmaceutical composition is administered to an individual who is a human.

28. The LSD1 inhibitor for use according to any one of claims 1 or 6-27, the pharmaceutical composition for use according to any one of claims 2 or 6-27, the method according to any one of claims 3 or 6-27 or the use according to any one of claims 4-27, wherein the LSD1 inhibitor or the pharmaceutical composition is administered orally.

29. The LSD1 inhibitor for use according to any one of claims 1 or 6-28, the pharmaceutical composition for use according to any one of claims 2 or 6-28, the method according to any one of claims 3 or 6-28 or the use according to any one of claims 4-28, wherein the LSD1 inhibitor or the pharmaceutical composition is administered in combination with one or more additional anti-cancer agents and / or with radiotherapy.

30. A product comprising a LSD1 inhibitor and one or more additional anti-cancer agents in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in treating NF1-mutant tumors.

31. A method of treating an NF1 -mutant tumor 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.

32. The article for use of claim 30 or the method of claim 31, wherein: - a LSD1 inhibitor as defined in any one of claims 6 to 14; and / or - a NF1 -mutant tumour as defined in any one of claims 15 to 24; and / or - a subject to which the preparation is administered as defined in any one of claims 25 to 27; and / or - The preparation is administered orally.

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