Therapeutic method for NF1 mutant tumors using LSD1 inhibitors

Abstract

The present invention relates to an LSD1 inhibitor for use in the treatment of NF1 mutant tumors, i.e., tumors having one or more mutations or genetic changes that affect the NF1 gene. The present invention similarly provides a method of treatment thereof in a subject in need of treatment of an NF1 mutant tumor, the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor.

Description

Technical Field

[0001] The present invention relates to the field of treatment of NF1 mutant tumors, i.e., tumors having one or more mutations or genetic changes that affect the NF1 gene. In particular, the present invention provides LSD1 inhibitors for use in the treatment of NF1 mutant tumors. The present invention also provides a method of treatment thereof in a subject in need of treatment of an NF1 mutant tumor, the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor.

Background Art

[0002] Tumors, particularly malignant tumors (cancers), are one of the leading causes of death worldwide. The clinical management of cancer has changed dramatically in the last few decades. Hitherto, cancer could only be treated with chemotherapeutic agents (less selective "dirty" drugs) that non-specifically (indiscriminately) limit cell proliferation by interfering with DNA and basic cell cycle mechanisms. Today, instead, a new approach of personalized precision medicine has been devised that blocks the growth of cancer cells with little damage to other cells in the body. The advantage of this approach is that targeted therapies are less harmful to normal cells.

[0003] Epigenetics is one of the emerging fields of cancer precision medicine, with first-generation drugs reaching the FDA approval and many more drugs in clinical trials. Lysine-specific demethylase 1 (LSD1 or KDM1A) is an epigenetic enzyme that regulates gene expression by demethylating two different residues of the histone H3 tail, namely lysine 4 (H3K4) and lysine 9 (H3K9), resulting in opposing effects. Demethylation of H3K4 is associated with transcriptional repression, while demethylation of H3K9 is associated with transcriptional activation. Furthermore, LSD1 is part of many multi-protein complexes that control enhancer-promoter contacts involved in gene repression, such as NurD and CoRest. LSD1 has been shown to play a major role in cancers such as leukemia and small cell lung cancer (SCLC), and significant efforts have been invested in the development of LSD1 inhibitors. Inhibitors targeting the catalytic active site, such as iadademstat, bomedemstat, and pulrodemstat, have been developed. These compounds bind deeply to the active site of LSD1 and inhibit both the catalytic activity and scaffolding interactions of LSD1 by blocking access to both the protein substrate (e.g., histone H3 tail) and non-substrate protein interactors (e.g., SNAG domain transcription factors). LSD1 inhibitors have been reported to have very potent anti-proliferative activity against specific tumor types and are currently in clinical trials as therapeutic agents for cancers such as acute myeloid leukemia (AML) and SCLC.

[0004] NF1 is a tumor suppressor gene mutated in tumors of neurofibromatosis type I (NF1), one of the most common single-gene disorders affecting approximately 1 in 3,000 people. This disorder is an autosomal dominant syndrome, and patients are characterized by a tendency to develop benign tumors called plexiform neurofibromas (PNs) that can eventually become malignant (malignant peripheral nerve sheath tumors - MPNSTs), as well as a tendency to develop various concomitant neurodevelopmental disorders such as cognitive and learning disabilities, epilepsy, speech disorders, autism, and hyperactivity. Patients with neurofibromatosis are also prone to developing various malignant tumors 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 frequently mutated in various cancers other than those associated with neurofibromatosis. Therefore, somatic mutations in the NF1 gene have been reported to occur with high frequencies, particularly in cutaneous melanoma (12 - 30%), acute myeloid leukemia (3.5 - 23.6%), ovarian cancer (12 - 34.4%), glioblastoma (14 - 23%), and squamous cell lung cancer (10.3 - 11%) (Philpott C et al., Hum Genomics, 2017, 11(1):13, doi:10.1186 / s40246-017-0109-3). Thus, mutations in the NF1 gene are involved in the development of various malignant tumors, whether or not the patient has neurofibromatosis type I. The protein product of the NF1 gene, neurofibromin, is a negative regulator of the RAS pathway, a signaling axis that promotes cell growth and division. The accepted hypothesis is that germline or somatic mutations in the NF1 gene contribute to cancer progression by impairing the negative control that neurofibromin exerts on RAS (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 large gene consisting of approximately 60 exons and encodes a large multi-domain protein consisting of more than 2,800 amino acids. Therefore, it is thought to have many functions that may be related to carcinogenesis in addition to RAS inhibition. Many malignant tumors caused in part by mutations in the NF1 gene have a very poor prognosis and still require targeted therapy.Therefore, the development of new treatment options for treating NF1-mutated tumors is of great interest both pharmaceutically and medically. The present invention addresses this need and other needs.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

[0006] The present invention is based on the surprising discovery that LSD1 inhibitors such as iadademstat, bomedemstat, and pulrodemstat are particularly beneficially effective in the treatment of NF1-mutated tumors, 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 further described in the sections of the following examples. Accordingly, the present invention provides a particularly beneficial and targeted therapeutic approach for treating NF1-mutated tumors.

[0007] Accordingly, the present invention relates to an LSD1 inhibitor for use in the treatment of NF1-mutated tumors. The present invention also relates to a pharmaceutical composition for use in the treatment of NF1-mutated tumors, comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients.

[0008] The present invention similarly provides a method for treating a subject in need of treatment of an NF1-mutated tumor, the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor (or a therapeutically effective pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients).

[0009] Furthermore, the present invention relates to the use of an LSD1 inhibitor for the treatment of an NF1-mutated tumor. The present invention further relates to the use of an LSD1 inhibitor for the manufacture of a medicament (or pharmaceutical composition) for the treatment of an NF1-mutated tumor.

[0010] As described above, the present invention is based on the surprising discovery that an LSD1 inhibitor is beneficially effective in the treatment of 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 further described and demonstrated in the examples section below. Thus, the exemplary LSD1 inhibitor, iadademstat, has been found to be very effective in various NF1-mutated tumor cell lines. Further LSD1 inhibitors having different chemical scaffolds and including both reversible and irreversible inhibitors of LSD1 have also been confirmed to be effective in the treatment of NF1-mutated tumors, as described in the examples section as well.

[0011] ​Accordingly, the present invention relates to an LSD1 inhibitor for use in the treatment of NF1 mutant tumors. The present invention also relates to a pharmaceutical composition for use in the treatment of NF1 mutant tumors, comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients. The present invention similarly provides a method of treatment in a subject in need of treatment of an NF1 mutant tumor, the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor (or a therapeutically effective amount of a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients). Further, the present invention relates to the use of an LSD1 inhibitor for the treatment of NF1 mutant tumors. The present invention further relates to the use of an LSD1 inhibitor for the manufacture of a medicament (or pharmaceutical composition) for the treatment of NF1 mutant tumors.

[0012] According to the present invention, an "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". Suitable LSD1 inhibitors include each of iadademstat or a pharmaceutically acceptable salt thereof (for example, iadademstat dihydrochloride), pruvudemstat or a pharmaceutically acceptable salt thereof (for example, pruvudemstat besilate), and bomedemstat or a pharmaceutically acceptable salt thereof (for example, bomedemstat bis tosylate). Particularly suitable LSD1 inhibitors are iadademstat or a pharmaceutically acceptable salt thereof (for example, iadademstat dihydrochloride).

[0013] The LSD1 inhibitor (for example, iadademstat or a pharmaceutically acceptable salt thereof) is preferably administered orally. Exemplary formulations that can be administered through oral administration, particularly oral ingestion, are described in more detail below.

[0014] The subject to be treated according to the present invention can be a human or an animal (for example, a non-human mammal), preferably a human. NF1 mutant tumors treated according to the present invention are any tumors that have one or more mutations or genetic changes (e.g., any one or more of the specific mutations / genetic changes mentioned or referenced below) that affect the NF1 gene, particularly any tumors that have one or more inactivating mutations or inactivating genetic changes that affect the NF1 gene (e.g., including any one of the specific types of tumors listed below). Thus, the present invention particularly relates to the treatment of NF1 mutant tumors that have one or more inactivating mutations or inactivating genetic changes in the NF1 gene. Such inactivating mutations or inactivating genetic changes that affect the NF1 gene particularly include loss-of-function mutations, which result in a decrease or absence of the expression and / or stability and / or activity of neurofibromin, its protein product. Further, such mutations or genetic changes can affect one or both alleles of the NF1 gene.

[0015] NF1 mutant tumors treated according to the present invention can be malignant (cancerous) or benign (non-cancerous). Further, malignant or benign NF1 mutant tumors can be solid or non-solid. NF1 mutant tumors are preferably NF1 mutant malignant tumors, i.e., NF1 mutant cancers.

[0016] 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 lymphoma, but also including NF1-mutated Burkitt lymphoma), NF1-mutated lung cancers (e.g., NF1-mutated small cell lung cancer (SCLC) or NF1-mutated non-small cell lung cancer (NSCLC), but also including NF1-mutated squamous cell lung cancer), NF1-mutated breast cancers (e.g., NF1-mutated triple-negative breast cancer), NF1-mutated esophageal-gastric cancers, NF1-mutated esophageal cancers, NF1-mutated gastric cancers, NF1-mutated gastrointestinal cancers, NF1-mutated colorectal cancers (e.g., NF1-mutated colorectal carcinomas), NF1-mutated liver cancers, NF1-mutated ovarian cancers, NF1-mutated uterine cancers (e.g., NF1-mutated uterine carcinomas), NF1-mutated cervical cancers (e.g., NF1-mutated cervical carcinomas), NF1-mutated pancreatic cancers, NF1-mutated prostate cancers (e.g., NF1-mutated prostatic adenocarcinomas), NF1-mutated bladder cancers (e.g., NF1-mutated bladder carcinomas), NF1-mutated pheochromocytomas, NF1-mutated head and neck cancers (e.g., NF1-mutated head and neck carcinomas), NF1-mutated neuroblastomas, NF1-mutated glioblastomas, NF1-mutated optic pathway gliomas, NF1-mutated skin cancers (e.g., NF1-mutated melanomas, but also including NF1-mutated desmoplastic melanomas), NF1-mutated malignant rhabdoid tumors, NF1-mutated rhabdomyosarcomas, NF1-mutated Ewing sarcomas, or NF1-mutated malignant peripheral nerve sheath tumors (MPNST), etc.

[0017] As described above, the NF1-mutated tumors to be treated are preferably NF1-mutated malignancies, but the present invention specifically also relates to the treatment of NF1-mutated benign tumors (which can also be referred to as NF1-mutated benign tumorous disorders) that constitute the same pathological condition. Examples of NF1-mutated benign tumors include, in particular, NF1-mutated plexiform neurofibromas, NF1-mutated ganglioneuromas, NF1-mutated iris nodules, or NF1-mutated cutaneous neurofibromas, etc. NF1-mutated benign tumors may also be NF1-mutated pre-cancerous tumors.

[0018] Particularly preferred examples of NF1 - mutant tumors treated according to the present invention are NF1 - mutant leukemia (e.g., NF1 - mutant AML or NF1 - mutant ALL), NF1 - mutant malignant rhabdoid tumors, NF1 - mutant lung cancer (e.g., NF1 - mutant SCLC), NF1 - mutant MPNST, or NF1 - mutant plexiform neurofibromas and the like.

[0019] Furthermore, the NF1 - mutant tumor to be treated may be an NF1 - mutant tumor that is not an NF1 - mutant MPNST (including the aforementioned specific types of malignant or benign NF1 - mutant tumors different from MPNST).

[0020] In humans, the NF1 gene is located on chromosome 17q11.2 and encodes a protein product called neurofibromin. The canonical (standard) amino acid sequence of isoform 2 of human neurofibromin is 2839 residues long (see, for example, Uniprot identifier P21359 - 1; https: / / www.uniprot.org / uniprot / P21359.fasta), and that of isoform 1 is 2818 residues long (see, for example, 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 found in most human tissues but not in neurons of the central nervous system. The NF1 gene can generate other alternative splicing isoforms by various combinations of its approximately 60 exons.

[0021] More than 3,000 germline mutations of 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 1,000 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 of the characterized mutations are loss-of-function, meaning that they ultimately have an adverse effect on the function of the protein product. At the gene level, all types of mutations have been reported, including nonsense, missense, frameshift, indels (insertions or deletions), microdeletions, inversions, splice-site variants, whole translocations, and complex rearrangements. However, there is no clear pattern of local mutational clustering within the NF1 gene. To identify mutations or genetic changes in the NF1 gene, it is recommended to apply a mutation detection pipeline to reliably characterize NF1 mutants. A series of different algorithms specifically fine-tuned to detect single nucleotide variants (SNVs), indels, or translocations in next-generation sequencing (NGS) reads are used there. The presence of mutations or genetic changes in the NF1 gene can be evaluated in samples obtained from the subject, such as biopsy samples.

[0022] The domain structure of neurofibromin is complex and, from the N-terminus to the C-terminus, (1) an N-heat domain containing, among other things, a cysteine- and serine-rich domain / GTPase-activating domain (CSRD) and a tubulin-binding domain (TBD); (2) a GTPase-activating domain (GAP)-related domain (GRD) that promotes the hydrolysis of active Ras-GTP to inactive Ras-GDP; (3) Sec14 identical segment; (4) Pleckstrin homology (PH)-like domain; and (5) C-heat domain containing a heat-like repeat domain (HLR) and a C-terminal domain (CTD) (wherein a syndecan binding domain (SBD) is found) comprising.

[0023] Furthermore, the Sec14, PH-like, and HLR domains form part of a so-called leucine-rich domain (LRD). The dimerization sites are found to be scattered within the N-heat domain (distal N-terminus and TBD), particularly within the C-heat domain.

[0024] In principle, NF1 mutant tumors to be treated according to the present invention may have one or more mutations or genetic changes (particularly one or more inactivating mutations or inactivating genetic changes) in the NF1 gene sequence for any one (or several) of the above domains or segments of the NF1 gene product neurofibromin.

[0025] Thus, for example, an NF1 mutant tumor can be an NF1 mutant tumor (e.g., NF1 mutant AML) having one or more inactivating mutations located in the domain related to the GTPase-activating domain (GAD) of NF1 (GRD).

[0026] In some embodiments, the NF1 mutant tumor has one or more inactivating mutations located in the cysteine- and serine-rich domain / GTPase-activating domain (CSRD) of NF1.

[0027] In some embodiments, the NF1 mutant tumor has one or more inactivating mutations located in the leucine-rich domain (LRD) of NF1. In some embodiments, the NF1 mutant tumor has one or more inactivating mutations located at at least one dimerization interface of NF1.

[0028] Furthermore, the present invention specifically relates to the treatment of NF1 mutant tumors in a subject determined (or diagnosed) to have an NF1 mutant tumor (e.g., any of the above specific or exemplary NF1 mutant tumors). In particular, the present invention also relates to a corresponding treatment (or corresponding method or use), which treatment comprises the steps of examining a subject having a tumor for one or more mutations or genetic changes (e.g., including any of the above mutations or genetic changes) that affect the NF1 gene, and, if such a mutation or genetic change is determined to be present, administering an LSD1 inhibitor to the subject in the next step.

[0029] Accordingly, the present invention provides an LSD1 inhibitor for use in the treatment of NF1 mutant tumors in a subject determined (or diagnosed) to have an NF1 mutant tumor. The present invention also relates to a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients for use in the treatment of NF1 mutant tumors in a subject determined (or diagnosed) to have an NF1 mutant tumor. The present invention likewise provides a method for treating NF1 mutant tumors in a subject determined (or diagnosed) to have an NF1 mutant tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of an LSD1 inhibitor (or a therapeutically effective amount of a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients). Furthermore, the present invention relates to the use of an LSD1 inhibitor for the treatment of NF1 mutant tumors in a subject determined (or diagnosed) to have an NF1 mutant tumor. The present invention further relates to the use of an LSD1 inhibitor for the manufacture of a medicament (or pharmaceutical composition) for the treatment of NF1 mutant tumors in a subject determined (or diagnosed) to have an NF1 mutant tumor.

[0030] Furthermore, the present invention also provides an LSD1 inhibitor for use in the treatment of NF1 mutant tumors, said use comprising the steps of examining a subject having a tumor for one or more mutations or genetic changes (e.g., including any of the above mutations or genetic changes) that affect the NF1 gene, and administering an LSD1 inhibitor to the subject if it is determined that such mutations or genetic changes affecting the NF1 gene are present. The present invention also relates to a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients for use in the treatment of NF1 mutant tumors, said use comprising the steps of examining a subject having a tumor for one or more mutations or genetic changes (e.g., including any of the above mutations or genetic changes) that affect the NF1 gene, and administering the pharmaceutical composition to the subject if it is determined that such mutations or genetic changes affecting the NF1 gene are present. The present invention similarly provides a method of treatment in a subject in need of treatment for NF1 mutant tumors, said method comprising the steps of examining a subject having a tumor for one or more mutations or genetic changes (e.g., including any of the above mutations or genetic changes) that affect the NF1 gene, and administering a therapeutically effective amount of an LSD1 inhibitor (or a therapeutically effective amount of a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients) to the subject if it is determined that such mutations or genetic changes affecting the NF1 gene are present. Further, the present invention also relates to the use of an LSD1 inhibitor for treating NF1 mutant tumors, said treatment comprising examining a subject having a tumor for one or more mutations or genetic changes (e.g., including any of the above mutations or genetic changes) that affect the NF1 gene, and administering an LSD1 inhibitor to the subject if it is determined that such mutations or genetic changes affecting the NF1 gene are present.The present invention further relates to the use of an LSD1 inhibitor for the manufacture of a medicament (or pharmaceutical composition) for the treatment of NF1 mutant tumors, said treatment comprising examining a subject having a tumor for one or more mutations or genetic changes affecting the NF1 gene (e.g., including any of the foregoing mutations or genetic changes), and, if it is determined that said mutation or genetic change affecting the NF1 gene is present, administering said medicament (or pharmaceutical composition) to said subject.

[0031] Mutations or genetic changes in the NF1 gene are a prominent feature of the hereditary disease neurofibromatosis type I, but such mutations or genetic changes contribute to the development of various tumors in subjects with or without neurofibromatosis type I. Thus, in some aspects, the present invention relates to the treatment of NF1 mutant tumors in subjects with neurofibromatosis type I. Accordingly, the present invention relates to an LSD1 inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitor) for use in the treatment of NF1 mutant tumors, said LSD1 inhibitor being administered to a subject with neurofibromatosis type I. Further, the present invention specifically relates to the treatment of NF1 mutant tumors in subjects without neurofibromatosis type I. Accordingly, in some aspects, the present invention relates to an LSD1 inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitor) for use in the treatment of NF1 mutant tumors, said LSD1 inhibitor (or pharmaceutical composition) being administered to a subject without neurofibromatosis type I.

[0032] The NF1 mutant tumor to be treated may further be a metastatic NF1 mutant malignancy, i.e., a metastatic NF1 mutant cancer. Thus, the NF1 mutant tumor to be treated can be a primary NF1 mutant cancer that has formed metastases, i.e., has spread to one or more other parts of the subject's body.

[0033] The NF1 mutant tumor to be treated may be a recurrent or refractory NF1 mutant cancer. The therapeutic effect of the LSD1 inhibitor in the treatment of NF1 mutant tumors can be further confirmed by additional in vitro or in vivo experiments as well as clinical trials in humans, which can be readily set up by those skilled in the art of drug development.

[0034] LSD1 inhibitor As used herein, the term "LSD1 inhibitor" means a compound / substance that reduces, decreases, blocks, or inhibits the gene expression, activity, or function of LSD1. Compounds that act as LSD1 inhibitors are known in the art. Any molecule that acts as an LSD1 inhibitor can in principle be used in the context of the present invention. Preferably, the LSD1 inhibitor is a small molecule. Furthermore, the LSD1 inhibitor can be an irreversible LSD1 inhibitor or a reversible LSD1 inhibitor. As demonstrated in the following examples section as well, both irreversible and reversible LSD1 inhibitors can be used for the treatment of NF1 mutant tumors according to the present invention. Typical irreversible LSD1 inhibitors are cyclopropylamine-based compounds such as iadademstat and bomedemstat, and these are used in Example 1 among the LSD1 inhibitors. A representative example of a reversible LSD1 inhibitor is the compound prodeumstat, which is also used in the examples section. Preferably, the LSD1 inhibitor is a selective LSD1 inhibitor, and as used herein, the term "selective LSD1 inhibitor" means an LSD1 inhibitor that exhibits at least 10-fold (preferably at least 100-fold) selectivity for LSD1 over other FAD-dependent monoamine oxidases, particularly MAO-A and MAO-B (this can be evaluated, for example, by determining the IC 50 values).

[0035] An exemplary list of small molecule LSD1 inhibitors is provided in the following table.

[0036]

Table A

[0037] The LSD1 inhibitor used according to the present invention can thus be, for example, any one of the specific compounds listed in the above table, or a pharmaceutically acceptable salt of any one of these compounds.

[0038] In some embodiments, the LSD1 inhibitor is, for example, 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, WO2013 / 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,Any one of the compounds disclosed in 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, US2022-0064126, CN103054869, CN103319466, CN104119280, CN105541806, CN105924362, CN105985265, CN106045862, CN106045881, CN106432248, CN106478639, CN106831489, CN106928235, CN107033148, CN107174584, CN107176927, CN107459476, CN107474011, CN107501169, CN107936022, CN108530302, CN109265462, CN109293664, CN109535019, CN110204551, CN110478352, CN111072610, CN111454252, CN112110936, CN112409310, CN112920130, CN113087712, CN113105479, CN113264903, CN113582906, CN113599380, CN114502561, CN114805205, CN114805261, KR20190040763, or KR20190040783, is an LSD1 inhibitor known in the art. Each of the above documents is incorporated herein by reference in its entirety (in particular,(including the compounds described in the Examples section of each of these documents). Accordingly, the LSD1 inhibitor may be, for example, a compound disclosed in any one of the above documents (including, for example, the Examples section of any one of these documents), and the compound can be used in the form of a non-salt form or a pharmaceutically acceptable salt form.,

[0039] In some embodiments, the LSD1 inhibitor is selected from the group consisting of iadademstat, prulademstat, bomedemstat, seclidemstat, 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, vafidemstat, 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 aforementioned compounds).

[0040] Iadademstat is a selective and irreversible LSD1 inhibitor. Iadademstat has the formula:

[0041] [Chemical formula]

[0042] The INN (International Nonproprietary Name) of the compound with [CAS Registry Number 1431304-21-0], also known as ORY-1001 or (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine. Iadademstat is described, for example, in Example 5 of WO2013 / 057322. Pharmaceutically acceptable salts of iadademstat including the hydrochloride salt (especially iadademstat dihydrochloride) are also described in WO2013 / 057322.

[0043] Purvodemstat has the formula:

[0044]

Chemical formula

[0045] A reversible LSD1 inhibitor with [CAS Registry Number 1821307-10-1], also known as CC-90011, having the chemical name 4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile. Purvodemstat is described, for example, in WO2015 / 168466 and WO2017 / 79670. Its pharmaceutically acceptable salts including besylate salt are also described therein.

[0046] Bomedemstat has the formula:

[0047]

Chemical formula

[0048] An irreversible LSD1 inhibitor with [CAS Registry Number 1990504-34-1], also known as IMG-7289, having the chemical name N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazol-1-yl)benzamide. Bomedemstat is described, for example, in WO2016 / 130952 and WO2018 / 35259. Its pharmaceutically acceptable salts, including the bis tosylate salt, are also described therein.

[0049] Secdemstat has the formula:

[0050]

Chem.

[0051] An LSD1 inhibitor with [CAS Registry Number 1423715-37-0], also known as SP-2577, having the chemical name (E)-N’-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide. Secdemstat is described, for example, in WO2013 / 025805 and WO2014 / 205213.

[0052] 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid is an irreversible LSD1 inhibitor and is described, for example, in WO2015 / 123465 and WO2017 / 27678. Its pharmaceutically acceptable salts, including the paratoluenesulfonate salt, are also described therein. The structure of this compound can be depicted as follows.

[0053]

Chem.

[0054] 3-(Cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide is an irreversible LSD1 inhibitor and is described, for example, in WO2020 / 047198. Its pharmaceutically acceptable salts are also described therein. The structure of this compound can be depicted as follows.

[0055]

Chemical formula

[0056] Bafidemstat is an irreversible LSD1 inhibitor of the formula:

[0057]

Chemical formula

[0058] and is 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. Bafidemstat is described, for example, in Example 35 of WO2012 / 13728.

[0059] 4-[5-[(3S)-3-Aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile is an LSD1 inhibitor described, for example, in WO2017 / 090756 (or EP3381896A1; see Example 37), WO2021 / 095835, WO2022 / 240886, and WO2023 / 054547. Among them are pharmaceutically acceptable salts of this compound, including benzoate (or benzoyl salt), sorbate, succinate, L-tartrate, hydrochloride, hemifumarate salt, monofumarate salt, hemioxalate salt, monooxalate salt, mesylate salt, esylate salt, or maleate salt. A specific solid form of this compound is described in WO2022 / 240886. This compound is also referred to as "TAS1440" in this specification. The structure of this compound can be depicted as follows.

[0060] [Chemical formula]

[0061] Further examples of LSD1 inhibitors include SYHA1807 or its pharmaceutically acceptable salts, or JBI-802 or its pharmaceutically acceptable salts. In some embodiments, the LSD1 inhibitor is selected from the group consisting of iadademstat, pruvudemstat, bomedemstat, seclidemstat, 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 their pharmaceutically acceptable salts.

[0062] In particular, the LSD1 inhibitor can be selected from the group consisting of iadademstat, prulodemstat, bomedemstat, seclidemstat, 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.

[0063] In a preferred embodiment, the LSD1 inhibitor is selected from the group consisting of iadademstat, prulodemstat, bomedemstat, and pharmaceutically acceptable salts thereof. In some embodiments, the LSD1 inhibitor is prulodemstat or a pharmaceutically acceptable salt thereof (e.g., prulodemstat besilate). In some embodiments, the LSD1 inhibitor is bomedemstat, or a pharmaceutically acceptable salt thereof (e.g., bomedemstat bis tosylate).

[0064] A particularly preferred LSD1 inhibitor is iadademstat or a pharmaceutically acceptable salt thereof. In some embodiments, iadademstat is used as the dihydrochloride salt (i.e., iadademstat dihydrochloride).

[0065] Unless otherwise specified, throughout this specification and the claims, any reference to an LSD1 inhibitor (e.g., iadademstat) includes not only the LSD1 inhibitor in non-salt form but also any pharmaceutically acceptable salt thereof. When the LSD1 inhibitor is iadademstat, it is preferably used in the form of a pharmaceutically acceptable salt, preferably the hydrochloride salt, more preferably the dihydrochloride salt.

[0066] Pharmaceutical preparation The LSD1 inhibitors used in accordance with the present invention, as well as any pharmaceutical composition containing the LSD1 inhibitors used in accordance with the present invention, can be administered by any route appropriate for the condition being treated. Exemplary routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, inhalation, intradermal, intrathecal, epidural, and infusion techniques), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal, etc. Preferably, the LSD1 inhibitor (or its corresponding pharmaceutical composition) is administered orally.

[0067] The LSD1 inhibitors used in accordance with the present invention can be administered in any convenient pharmaceutical composition or formulation, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions / formulations can contain conventional ingredients in pharmaceutical manufacture, such as diluents, carriers, pH adjusters, preservatives, solubilizers, stabilizers, wetting agents, emulsifying agents, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, antioxidants, and / or additional active drugs. They can further contain other therapeutically effective or therapeutically valuable substances.

[0068] Typical formulations are manufactured by mixing an LSD1 inhibitor with one or more pharmaceutically acceptable excipients. Suitable excipients are well known to those skilled in the art and are described in detail, for example, in “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 formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow promoters, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and / or other known additives for improving the appearance of the active drug or for assisting in the manufacture of the pharmaceutical (i.e., the medicine).

[0069] For oral delivery, the LSD1 inhibitor can be formulated in a preparation containing a pharmaceutically acceptable carrier, such as a binder (e.g., gelatin, cellulose, or tragacanth gum), 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 sweetening or flavoring agent (e.g., glucose, sucrose, saccharin, methyl salicylate, or peppermint). The preparation can be administered orally, for example, in the form of a sealed gelatin capsule or a compressed tablet. Capsules and tablets can be manufactured by any prior art method. Capsules and tablets can also be coated with various coatings known in the art to modify the flavor, taste, color, and shape of the capsules and tablets. Additionally, a liquid carrier such as a fatty oil can be included in the capsule.

[0070] Suitable oral formulations may be in the form of suspensions, syrups, chewing gums, wafers, elixirs, etc. If desired, conventional agents for changing the form of flavor, taste, color, and shape may also be included. Further, when it is convenient to administer to a subject with dysphagia by an enteral nutrition tube, the active compound can also be dissolved in an acceptable lipophilic vegetable oil vehicle, such as olive oil, corn oil, or safflower oil.

[0071] The LSD1 inhibitor can also be administered parenterally in the form of a solution or suspension, or in a lyophilized form that can be converted to a solution or suspension before use. In such formulations, diluents or pharmaceutically acceptable carriers, such as sterile water and physiological saline buffers, can be used. All other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants, and antioxidants can also be included. For example, as active ingredients, sodium chloride, acetic acids, citrate or phosphate buffers, glycerin, dextrose, fixed oils, methylparaben, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, etc. can be mentioned. The parenteral formulation can be stored in any conventional container, such as vials and ampoules.

[0072] Subcutaneous implantation for sustained release of the LSD1 inhibitor can also be a suitable route of administration. This requires a surgical procedure for implanting the LSD1 inhibitor of any suitable formulation into a subcutaneous cavity, such as under the lower anterior abdominal wall. See, for example, Wilson et al., (1984) J. Clin. Psych. 45: 242-247. Hydrogels can be used as carriers for the sustained release of the LSD1 inhibitor. Hydrogels are generally known in the art. They are typically produced by crosslinking high molecular weight biocompatible polymers into a network, which swells with water and forms a gel-like substance. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purposes of the present invention, hydrogels made of polyethylene glycol, collagen, or poly(glycol-co-L-lactic acid) may be useful. See, for example, Phillips et al., (1984) J. Pharmaceut. Sci., 73: 1718-1720.

[0073] Pharmaceutical compositions, such as oral and parenteral compositions, can be formulated into unit dosage forms for ease of administration and uniform dosage. As used herein, "unit dosage form" refers to a physically discrete unit suitable as a unit dose for administration to a subject, and each unit contains a predetermined amount of an active ingredient calculated to produce the desired therapeutic effect, together with one or more suitable pharmaceutical carriers.

[0074] Suitable oral dosage forms of iadademstat are disclosed, for example, in WO2019 / 211491. In particular, iadademstat can be provided in the form of solid oral dosage forms, such as tablets or capsules. Alternatively, iadademstat may be provided in the form of an oral liquid composition, particularly an oral solution, such as an oral aqueous solution (corresponding oral solutions containing oral aqueous solutions can be prepared, for example, from powders for reconstitution). As described above, iadademstat is preferably used in the form of iadademstat dihydrochloride.

[0075] In the treatment of NF1 mutant tumors, the LSD1 inhibitor (or corresponding pharmaceutical composition) can be administered in any suitable manner as determined by an expert in the medical field. Suitable dosages and suitable treatment periods and frequencies of administration can vary within wide limits and are determined, inter alia, by factors such as the condition of the subject, the specific type and severity of the disease, the particular form of the active ingredient, and the method of administration. In general, with a suitable dosage and treatment regimen, the LSD1 inhibitor is provided in an amount sufficient to provide a therapeutic benefit, such as an improved clinical outcome, such as more frequent complete or partial remissions, or a longer disease-free period and / or overall survival, or a reduction in the severity of symptoms, or any other objectively confirmable improvement noticed by the clinician. The therapeutically effective amount can generally be evaluated or estimated using experimental models such as dose-response curves derived from in vitro or animal model test systems, or from human clinical trials.

[0076] As is well known to those skilled in the art, the appropriate dosage and administration schedule of an LSD1 inhibitor depend on the specific LSD1 inhibitor used, its LSD1 inhibitory ability, its pharmacokinetic profile, and other factors.

[0077] Iadademstat is a highly potent active pharmaceutical ingredient (HPAPI). Therefore, the expected daily dose is very low, for example, less than 1 mg per day. Accordingly, the drug load in pharmaceutical formulations (including, for example, solid oral forms) is also typically very low (for example, less than 1 mg of API per 100 mg of solid oral form). Generally, for oral administration to adult human subjects (i.e., human subjects 18 years of age or older), the daily dose of about 50 μg to about 300 μg, preferably about 75 μg to 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 about 300 μg, or any range between any two of the aforementioned daily doses) of iadademstat described herein should be appropriate, but these limits can be adjusted if necessary. For example, the aforementioned doses can be reduced in the case of oral administration to pediatric subjects, especially human subjects less than 18 years of age (for example, 0 to 2 years old, 2 to 12 years old, or less than 12 to 18 years old). As used herein, the term "μg" (or "ug") refers to micrograms.

[0078] In some embodiments, the LSD1 inhibitor is iadademstat (or a pharmaceutically acceptable salt thereof, such as iadademstat dihydrochloride) and is administered on a 5 days on / 2 days off (5 / 2) schedule.

[0079] In some embodiments, the LSD1 inhibitor is iadademstat (or a pharmaceutically acceptable salt thereof, such as iadademstat dihydrochloride), and is orally administered to adult human subjects 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), on a 5-day dosing / 2-day rest (5 / 2) schedule. The dosages reflected herein for iadademstat relate to the corresponding amounts of the iadademstat free base. In some embodiments, iadademstat is orally administered at a daily dose of about 75 μg on a 5-day dosing / 2-day rest (5 / 2) schedule. In some embodiments, iadademstat is orally administered at a daily dose of about 100 μg on a 5-day dosing / 2-day rest (5 / 2) schedule. In some embodiments, iadademstat is orally administered at a daily dose of about 150 μg on a 5-day dosing / 2-day rest (5 / 2) schedule. In some embodiments, iadademstat is orally administered at a daily dose of about 200 μg on a 5-day dosing / 2-day rest (5 / 2) schedule. In some embodiments, iadademstat is orally administered at a daily dose of about 250 μg on a 5-day dosing / 2-day rest (5 / 2) schedule. In some embodiments, iadademstat is orally administered at a daily dose of about 300 μg on a 5-day dosing / 2-day rest (5 / 2) schedule. As described above, these dosages can be reduced in the case of pediatric use.

[0080] Combination therapy The LSD1 inhibitor used in accordance with the present invention can be administered in monotherapy (single-agent therapy) (e.g., without co-administering any additional therapeutic agent or without co-administering any additional anti-cancer agent). Accordingly, the present invention relates to an LSD1 inhibitor (or a pharmaceutical composition comprising an LSD1 inhibitor and optionally one or more pharmaceutically acceptable excipients) for use in monotherapy of NF1 mutant tumors (preferably NF1 mutant cancers). The present invention similarly relates to the corresponding methods and uses for monotherapy of NF1 mutant tumors (preferably NF1 mutant cancers).

[0081] However, the LSD1 inhibitor can also be administered in combination with one or more additional therapeutic agents, particularly one or more additional anti-cancer agents. When the LSD1 inhibitor is used in combination with an additional anti-cancer agent, the dosage of each compound may be different from when the corresponding compound is used alone. In particular, one or both of the compounds can be used at a low dosage.

[0082] The combination of an LSD1 inhibitor and one or more additional therapeutic agents (such as one or more additional anti-cancer agents) can include co-administering / co-dosing the LSD1 inhibitor and the additional therapeutic agent either in a single pharmaceutical formulation or in separate pharmaceutical formulations, or administering / dosing the LSD1 inhibitor and the additional therapeutic agent sequentially / separately. When the administration is sequential, either the LSD1 inhibitor or one or more of the additional therapeutic agents can be administered first. When the administration is simultaneous, the one or more additional therapeutic agents can be included in the same pharmaceutical formulation as the LSD1 inhibitor or can be administered in two or more distinct / separate pharmaceutical formulations. It will also be understood that administering the LSD1 inhibitor and the additional therapeutic agent in separate pharmaceutical formulations can be advantageous, for example, when each agent is administered using a different route and / or a different dosing schedule / regimen.

[0083] Furthermore, the LSD1 inhibitor can also be administered in combination with physical therapy, particularly radiation therapy. The present invention also relates to the combined use of an LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and physical therapy (particularly radiation therapy). Physical therapy (or radiation therapy) can be initiated before, after, or simultaneously with the administration of the LSD1 inhibitor (e.g., about 1 to 72 hours before or after the administration of the LSD1 inhibitor).

[0084] Accordingly, the present invention relates to an LSD1 inhibitor for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers) in combination with one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and / or in combination with radiotherapy. The present invention also relates to a pharmaceutical composition 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) in combination with one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and / or in combination with radiotherapy. The present invention further relates to an LSD1 inhibitor (or a pharmaceutical composition 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 the pharmaceutical composition comprising the LSD1 inhibitor) is administered in combination with one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and / or in combination with radiotherapy. The present invention further relates to an LSD1 inhibitor (or a pharmaceutical composition 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 the pharmaceutical composition comprising the LSD1 inhibitor) is used in combination with one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and / or in combination with radiotherapy. The present invention further relates to (i) an anti-cancer agent for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers) in combination with an LSD1 inhibitor; (ii) an anti-cancer agent for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers), wherein the anti-cancer agent is co-administered with an LSD1 inhibitor; or (iii) an anti-cancer agent for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers), wherein the anti-cancer agent is for use in combination with an LSD1 inhibitor.

[0085] The present invention also provides a method of treating a subject in need of treatment for an NF1-mutated tumor (preferably an NF1-mutated cancer), the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor (or a therapeutically effective pharmaceutical composition comprising an 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 radiation therapy.

[0086] Furthermore, the present invention relates to the use of an LSD1 inhibitor for the treatment of an NF1-mutated tumor (preferably an NF1-mutated cancer) in combination with one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) and / or in combination with radiation therapy. The present invention also relates to the use of an anti-cancer agent for the treatment of an NF1-mutated tumor (preferably an NF1-mutated cancer) in combination with an LSD1 inhibitor.

[0087] The present invention further relates to the use of an LSD1 inhibitor for manufacturing a medicament (or pharmaceutical composition) for treating NF1 mutant tumors (preferably NF1 mutant cancers) in combination with one or more further therapeutic agents (in particular one or more further anti-cancer agents) and / or in combination with radiotherapy. The present invention also relates to the use of an anti-cancer agent for manufacturing a medicament for treating NF1 mutant tumors (preferably NF1 mutant cancers) in combination with an LSD1 inhibitor. The present invention similarly relates to the use of an LSD1 inhibitor and one or more further anti-cancer agents for manufacturing a medicament for treating NF1 mutant tumors (preferably NF1 mutant cancers), wherein the medicament in this case comprises the LSD1 inhibitor and the further anti-cancer agent(s) in the same pharmaceutical formulation or in separate pharmaceutical formulations. The present invention also relates to the use of an LSD1 inhibitor for manufacturing a medicament for treating NF1 mutant tumors (preferably NF1 mutant cancers), wherein the medicament in this case is manufactured for use in combination (or in combination use) with one or more further therapeutic agents (in particular one or more further anti-cancer agents) and / or radiotherapy. The present invention also relates to the use of an anti-cancer agent for manufacturing a medicament for treating NF1 mutant tumors (preferably NF1 mutant cancers), wherein the medicament in this case is manufactured for use in combination (or in combination use) with an LSD1 inhibitor.

[0088] The present invention further provides a combined product comprising an LSD1 inhibitor and one or more further therapeutic agents (in particular one or more further anti-cancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers). Thus, the LSD1 inhibitor and the further therapeutic agent (in particular the further anti-cancer agent(s)) may be present in a single pharmaceutical formulation (i.e., in the same pharmaceutical formulation) or provided in separately distinct (separate) pharmaceutical formulations.

[0089] The present invention also provides a pharmaceutical composition comprising an LSD1 inhibitor in combination with one or more further therapeutic agents (in particular one or more further anti-cancer agents) and one or more pharmaceutically acceptable excipients for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers).

[0090] The present invention further provides an article of manufacture (or kit) comprising an LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers).

[0091] The present invention further provides a method of treatment in a subject in need of treatment of an NF1 mutant tumor (preferably NF1 mutant cancer), the method comprising administering to the subject a therapeutically effective amount of the above combination product, pharmaceutical composition or article of manufacture. In particular, the present invention provides a method of treatment in a subject in need of treatment of an NF1 mutant tumor (preferably NF1 mutant cancer), the method comprising administering to the subject a therapeutically effective amount of a combination product comprising an LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) in the same pharmaceutical formulation or in separate pharmaceutical formulations. The present invention further provides a method of treatment in a subject in need of treatment of an NF1 mutant tumor (preferably NF1 mutant cancer), the method comprising administering to the subject a therapeutically effective amount of an LSD1 inhibitor and a therapeutically effective amount of one or more additional therapeutic agents (particularly one or more additional anti-cancer agents).

[0092] The present invention further provides the use of a combination comprising an LSD1 inhibitor and one or more additional therapeutic agents (particularly one or more additional anti-cancer agents) for the manufacture of a medicament (or pharmaceutical composition) for treating NF1 mutant tumors (preferably NF1 mutant 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 anti-cancer agents) for treating NF1 mutant tumors (preferably NF1 mutant cancers).

[0093] The anti-cancer agent(s) (in particular, the "anti-cancer agent" or "one or more additional anti-cancer agents" mentioned in any of the above paragraphs) are, for example, MEK inhibitors (in particular, inhibitors of MEK1 and / or MEK2; for example, selumetinib), Pi3K inhibitors (for example, copanlisib), mTOR inhibitors (for example, temsirolimus), ERK inhibitors (in particular, inhibitors of ERK1 and / or ERK2; for example, ulixertinib), kRAS inhibitors (for example, sotorasib), EGFR inhibitors (for example, lapatinib), cKIT inhibitors (for example, imatinib), proteasome inhibitors (for example, bortezomib), DNA intercalators (for example, doxorubicin), RAF inhibitors (in particular, BRAF inhibitors; for example, sorafenib), VEGFR inhibitors (for example, cabozantinib), ALK inhibitors (for example, crizotinib), glutaminase inhibitors (for example, telaglenastat), JAK inhibitors (or Janus kinase inhibitors; for example, tofacitinib), PLK1 inhibitors (for example, volasertib), Bcl2 inhibitors (for example, venetoclax), HDAC inhibitors (for example, vorinostat), HSP90 inhibitors (for example, onalespib), Wnt / β-catenin pathway inhibitors (for example, OMP-18R5), aurora kinase inhibitors (for example, alisertib), MDM2 inhibitors (for example, alrizomadlin), CDK4 / 6 inhibitors (for example, abemaciclib), YAP / TAZ pathway inhibitors (for example, pazopanib), SOS inhibitors (for example, BI 1701963), Grb2 inhibitors (for example, BP1001), BET inhibitors (in particular, including BRD4 inhibitors;For example, it can be selected from a GSK1210151A), an AKT inhibitor (e.g., ipatasertib), a MNK inhibitor (e.g., ETC-206), an NTRK inhibitor (e.g., entrectinib), a SPH2 inhibitor (e.g., JAB-3068), and a PP2A inhibitor (e.g., LB100).;

[0094] The MEK inhibitor can be, for example, selumetinib, trametinib, cobimetinib, binimetinib, mirdametinib, pimasertib, refametinib, zapnometinib, avutometinib, HL-085, FCN-159, TAK-733, or a pharmaceutically acceptable salt of any one of these agents. The Pi3K inhibitor can be, for example, copanlisib, alpelisib, idelalisib, duvelisib, umbralisib, buparlisib, zandelisib, linperlisib, parsaclisib, leniolisib, paxalisib, inavolisib, serabelisib, pictilisib, taselisib, tenalisib, eganelisib, GSK2636771, MEN1611, AMG-319, or a pharmaceutically acceptable salt of any one of these agents. The mTOR inhibitor can be, for example, temsirolimus, everolimus, sirolimus, or a pharmaceutically acceptable salt of any one of these agents. The ERK inhibitor can be, for example, ulixertinib or a pharmaceutically acceptable salt thereof. The kRAS inhibitor can be, for example, sotorasib, adagrasib, or a pharmaceutically acceptable salt of any one of these agents. The EGFR inhibitor can be, for example, lapatinib, gefitinib, erlotinib, osimertinib, afatinib, or a pharmaceutically acceptable salt of any one of these agents.The cKIT inhibitor can be, for example, imatinib, sorafenib, lapatinib, sunitinib, or a pharmaceutically acceptable salt of any one of these agents. The proteasome inhibitor can be, for example, bortezomib, carfilzomib, ixazomib, or a pharmaceutically acceptable salt of any one of these agents. The DNA intercalator can be, for example, doxorubicin, daunorubicin, epirubicin, idarubicin, or a pharmaceutically acceptable salt of any one of these agents. The RAF inhibitor can be, for example, sorafenib, encorafenib, dabrafenib, vemurafenib, or a pharmaceutically acceptable salt of any one of these agents. The VEGFR inhibitor can be, for example, cabozantinib, axatinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib, or a pharmaceutically acceptable salt of any one of these agents. The ALK inhibitor can be, for example, crizotinib, alectinib, ceritinib, or a pharmaceutically acceptable salt of any one of these agents. The glutaminase inhibitor can be, for example, telaglenastat or its pharmaceutically acceptable salt. The JAK inhibitor can be, for example, tofacitinib, ruxolitinib, upadacitinib, abrocitinib, or a pharmaceutically acceptable salt of any one of these agents. The PLK1 inhibitor can be, for example, volasertib, onvansertib, rigosertib, BI 2536, or a pharmaceutically acceptable salt of any one of these agents.The Bcl2 inhibitor can be, for example, venetoclax, navitoclax, obatoclax, or a pharmaceutically acceptable salt of any one of these agents. The HDAC inhibitor can be, for example, vorinostat, belinostat, panobinostat, romidepsin, practinostat, rocilinostat, quisinostat, abexinostat, resminostat, givinostat, entinostat, mocetinostat, or a pharmaceutically acceptable salt of any one of these agents. The HSP90 inhibitor can be, for example, onalespib, luminespib, ganetespib, geldanamycin, IPI-504, tanespimycin, alvespimycin, or a pharmaceutically acceptable salt of any one of these agents. The Wnt / β-catenin pathway inhibitor can be, for example, OMP-18R5, OMP-54F28, OTSA 101, SAH-BCL9, XAV939, IWR1, JW74, J01-017a, PKF115-584, PKF118-310, NCB-0846, LGK974, CWP232291, PRI-724, sulindac, vismodegib, glasdegib, or a pharmaceutically acceptable salt of any one of these agents. The aurora kinase inhibitor can be, for example, alisertib, tozasertib, barasertib, danusertib, or a pharmaceutically acceptable salt of any one of these agents.The MDM2 inhibitor can be, for example, alrizomadoline, idasanutlin, RO5045337, RO5503781, AMG232, CGM097, SAR405838, MK-8242, ALRN-6924, or a pharmaceutically acceptable salt of any one of these agents. The CDK4 / 6 inhibitor can be, for example, abemaciclib, ribociclib, palbociclib, or a pharmaceutically acceptable salt of any one of these agents. The YAP / TAZ pathway inhibitor can be, for example, K-975, TED-347, pazopanib, or a pharmaceutically acceptable salt of any one of these agents. The SOS inhibitor can be, for example, BI 1701963, BI 3406, BAY-293, or a pharmaceutically acceptable salt of any one of these agents. The Grb2 inhibitor can be, for example, BP1001, CGP78850, CGP85793, or a pharmaceutically acceptable salt of any one of these agents. The BET inhibitor can be, for example, ABBV-075, ABBV-744, AZD5153, BAY1238097, CPI-203, CPI-0610, GSK1210151A (or I-BET 151), GSK1324726A (I-BET 726), GSK525762 (or I-BET 762), JQ1, LY294002, MS 436, MS 645, MT-1, olinone, OTX-015, RVX-208, TEN-010, or a pharmaceutically acceptable salt of any one of these agents. The AKT inhibitor can be, for example, ipatasertib, uprosertib, afuresertib, MK-2206, triciribine, lactoquinomycin, AZD5363, miransertib, capibasertib, or a pharmaceutically acceptable salt of any one of these agents. The MNK inhibitor can be, for example, ETC-206, SEL-201, BAY1143269, tomivosertib, CGP57380, or a pharmaceutically acceptable salt of any one of these agents.The NTRK inhibitor can be, for example, entrectinib, larotrectinib, or a pharmaceutically acceptable salt of any one of these agents. The SPH2 inhibitor can be, for example, JAB-3068, TNO155, SHP099, RMC-4550, IACS-13909, or a pharmaceutically acceptable salt of any one of these agents. The PP2A inhibitor can be, for example, LB100, cantharidin, cantharidic acid, cytostatin, fostriecin, or a pharmaceutically acceptable salt of any one of these agents. In principle, any of the above anticancer agents can be used in either the non-salt form or in the form of a pharmaceutically acceptable salt. The present invention relates specifically and individually to each LSD1 inhibitor described herein in combination with each of the above anticancer agents.

[0095] As described above, one or more additional therapeutic agents used in combination with an LSD1 inhibitor according to the present invention can be (or can include) one or more additional anticancer agents. Alternatively, or in addition, one or more additional therapeutic agents may include an antiemetic. Accordingly, the present invention also relates to an LSD1 inhibitor for use in the treatment of NF1 mutant tumors (preferably NF1 mutant cancers) in combination with one or more additional anticancer agents and also in combination with an antiemetic (and optionally also in combination with radiotherapy); the present invention similarly relates to corresponding methods and uses (including all of the above methods and uses) comprising the combined administration of an LSD1 inhibitor, one or more additional anticancer agents, and an antiemetic. The antiemetic can be, for example, 5-HT 3An antagonist (or “setron”), for example, palonosetron (optionally in combination with netupitant), ramosetron, alosetron, ondansetron, tropisetron, granisetron, dolasetron, azasetron, bemesetron, cilansetron, lerisetron, ricasetron, or zatosetron; olanzapine; a corticosteroid, for example, methylprednisolone or dexamethasone; or prochlorperazine may be used.

[0096] Manufactured article The pharmaceutical composition (or formulation) of the present invention can be placed in a container, pack, or dispenser, together with instructions for administration.

[0097] Accordingly, in a further aspect, the present invention provides an article of manufacture containing an LSD1 inhibitor or a pharmaceutical composition containing an LSD1 inhibitor for treating NF1 mutant tumors as described herein.

[0098] In some aspects, the article of manufacture includes a container and a pharmaceutical composition for use in accordance with the present invention as described herein. In some aspects, the present invention provides an article of manufacture (or kit) comprising a container and a combination product (as described above) for use in the treatment of NF1 mutant tumors (particularly NF1 mutant cancers). The present invention also provides an article of manufacture (or kit) comprising (i) a first container containing an LSD1 inhibitor, (ii) a second container containing a further anti-cancer agent (as described above), and (iii) optionally, one or more further containers containing one or more further anti-cancer agents for use in the treatment of NF1 mutant tumors (particularly NF1 mutant cancers).

[0099] The manufactured article may further include a label or package insert. The term "package insert" refers to the instructions customarily included in the package of a commercially available therapeutic product and contains information regarding indications, usage, dosage, administration, contraindications, and / or warnings about the use of such a therapeutic product. Suitable containers are, for example, blister packs, bottles, vials, syringes, etc. The container can be formed from various materials such as glass or plastic. The container can hold a composition or formulation effective in treating a disease and can also be provided with a sterile access port (for example, the container can be a bag or vial for intravenous solutions having a stopper that can be penetrated by a hypodermic needle). The label or package insert indicates that this composition is used for the treatment of a selected disease, particularly NF1 mutant tumors. Alternatively or additionally, the manufactured article can further include a second container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. Further, other materials desirable from a commercial and user perspective, such as other buffers, diluents, filters, needles, and syringes, may be included.

[0100] The manufactured article or kit may further include instructions regarding the co-administration of one or more additional anti-cancer agents (as described above). For example, if the kit includes a first pharmaceutical composition / formulation containing an LSD1 inhibitor and a second pharmaceutical composition / formulation containing an additional anti-cancer agent, the kit may further include instructions regarding the simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions / formulations to a subject in need thereof.

[0101] In another aspect, the manufactured article is suitable for the delivery of a solid oral dosage form of an LSD1 inhibitor, such as a tablet or capsule. Such a manufactured article preferably includes several unit dosage forms. Such a manufactured article may include a card having dosage forms arranged in the order of their intended use. An example of such a manufactured article is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals. If desired, the days of the treatment schedule on which the dosage forms can be administered can also be specified in the form of numbers, letters, or other marks or using a calendar fold-out to assist with memory.

[0102] According to one aspect, the manufactured article or kit may include: (i) a first container containing an LSD1 inhibitor; (ii) a second container containing a further anti-cancer agent; and optionally (iii) a third container containing a further anti-cancer agent. In this case, the anti-cancer agent in the third container is different from the anti-cancer agent in the second container. Alternatively, or additionally, the kit may include another container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. Further, other materials that are desirable from a commercial and user perspective, such as other buffers, diluents, filters, needles, and / or syringes, may be included.

[0103] When the manufactured article or kit includes a composition of an LSD1 inhibitor and a composition of a further anti-cancer agent, the kit may include 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 includes instructions for administering the separate components. The kit form is particularly beneficial when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when they are administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing physician or veterinarian.

[0104] Definition Unless otherwise defined, 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 pertains.

[0105] The following definitions apply throughout this specification and the claims, unless otherwise specified. For the purposes of the present invention, "subject" (or "patient") includes both humans and other animals, particularly mammals. Accordingly, the methods and uses of the present invention are applicable to both human therapy and veterinary applications. In a preferred embodiment, the subject (or patient) is a mammal (e.g., a human or a non-human mammal), most preferably the subject is a human (e.g., a male or female human). The human subject may be of any age, including, for example, 0 - 2 years old, 2 - 12 years old, 12 - 18 years old, or 18 years old and above.

[0106] The terms "treatment", "treating", etc. are generally used herein to mean obtaining the desired pharmacological and / or physiological effect. This includes partial or complete cure or amelioration of a disease (such as an NF1 - mutated tumor) and / or the symptoms or adverse effects resulting from the disease, or partial or complete arrest of the progression of the disease and / or the symptoms or adverse effects resulting from the disease. The term "treatment" as used herein encompasses any treatment of a disease (such as an NF1 - mutated tumor) in a subject. For example, it includes, but is not limited to, inhibition of the disease, i.e., halting, delaying or slowing its onset / progression; or alleviation of the disease, i.e., bringing about its (complete or partial) regression, remission, correction or reduction. The present invention pertains specifically and expressly to each of these forms of treatment.

[0107] As used herein, the terms "therapeutically effective amount" or "effective amount" of a compound according to the present invention (particularly an LSD1 inhibitor) refer to an amount sufficient to produce a desired biological effect (e.g., a therapeutic effect or benefit) in a subject. Thus, a therapeutically effective amount of a compound may be an amount sufficient to treat a disease (such as an NF1 mutant tumor) in a subject suffering from or susceptible to that disease, and / or to delay the onset or progression of the disease, and / or to alleviate one or more symptoms of the disease. The therapeutically effective amount will vary depending on the compound, the state of the disease being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0108] The term "pharmaceutically acceptable" means the properties of a material that is useful in the manufacture of a pharmaceutical composition, is generally safe, non-toxic, biologically and otherwise not harmful, and is acceptable for veterinary and / or human pharmaceutical use.

[0109] As used herein, "pharmaceutically acceptable salts" are meant to include salts of the free acids and / or bases of particular compounds that retain the biological effectiveness of the particular compound and are not biologically or otherwise undesirable. Since compounds may have one or more sufficiently acidic or sufficiently basic functional groups, or both, they can react with any of several inorganic or organic bases, and inorganic or organic acids, to form pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts include salts produced by reacting the compounds described herein (particularly LSD1 inhibitors, such as iadademstat) with a mineral 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, caprylate, acrylate, formate, isobutyrate, caproate, 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 an LSD1 inhibitor) has an acidic moiety, suitable pharmaceutically acceptable salts can 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, and the like.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 the references cited therein, all of which are incorporated herein by reference).

[0110] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and mean a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient (pharmaceutically active ingredient) (especially an LSD1 inhibitor) together with one or more pharmaceutically acceptable excipients, which is administered to a subject (e.g., a human) in need thereof.

[0111] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” can be used interchangeably and refers to any pharmaceutically acceptable component in a pharmaceutical composition that has no therapeutic activity and is non - toxic to the subject to which it is administered. For example, disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, etc. used in the formulation of pharmaceuticals. They are generally safe for human administration according to established government standards, including those promulgated by the US Food and Drug Administration and / or the European Medicines Agency. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art.

[0112] As used herein, the term “inhibitor” refers to a compound that competes with, reduces, blocks, inhibits, abrogates, or interferes with, in some way, the binding of a specific ligand to a specific receptor or enzyme, and / or in some way reduces, blocks, inhibits, abrogates, or interferes with the activity or function of a specific protein, such as a receptor or enzyme.

[0113] As used herein, “small molecule” refers to an organic compound having a molecular weight of 900 Da (dalton) or less, preferably less than 500 Da. Molecular weight is the mass of a molecule, calculated by multiplying the atomic weight of each constituent element in the molecular formula by the number of atoms of that element.

[0114] In this specification, the term "comprising" (or "comprise", "comprises", "contain", "contains", or "containing") has the meaning of "including, in particular", that is, "including... among any further elements", unless otherwise specified or the context dictates otherwise. In addition to this, this term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprising B and C" has the meaning of "A including, in particular, B and C", and A can also contain any further elements (for example, "A containing B, C, and D" is also included), but this term also includes the meanings of "A consisting essentially of B and C" and "A consisting of B and C" (that is, other components other than B and C are not included in A).

[0115] In this specification, the indefinite articles "a" and "an" and the definite article "the" include not only singular referents but also plural referents, unless the context clearly dictates otherwise.

[0116] The term "about" or "approximately" means an acceptable error with respect to a particular value determined by a person skilled in the art. The error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means 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. Any reference to a numerical value or range provided with the term "about" also includes a reference to the corresponding specific value or range.

[0117] Furthermore, whenever a numerical range is provided / described herein, it should be understood that all values and sub-ranges subsumed within each numerical range are specifically provided by the present invention. Accordingly, the present invention relates specifically and individually to each value falling within the numerical ranges described herein and to each and every sub-range subsumed by the numerical ranges described herein.

[0118] In this specification, various compounds are described by their chemical formulas and their corresponding chemical names. In the event of any discrepancy between any chemical formula shown herein and its corresponding chemical name, the present invention relates specifically and individually to the compound defined by the chemical formula and the compound defined by the chemical name.

[0119] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

Examples

[0120] The following examples are provided to illustrate the present invention. These should not be regarded as limiting the scope of the present invention, but rather should be regarded merely as representative of the present invention. Example 1: Effect of LSD1 inhibitor on NF1 mutant tumor cell lines Experimental Design Mycoplasma - free tumor cell lines of various tumor types with mutations in the NF1 gene (see Table 1) were seeded at the optimal cell density to ensure logarithmic growth throughout the experimental period (see Table 2) in 50 μl / well of complete medium in a 96 - well plate (all reagents are from Thermo Fisher as described in Table 2). On the day after seeding, 50 μl of medium containing nine serial dilutions (1:3) of 2 - fold concentrated iadademstat (LSD1 inhibitor, used as the dihydrochloride salt) was added to the cells, and 100 μl of cells treated with the 1 - fold concentrated compound at each dilution concentration was obtained. Furthermore, the effects of other LSD1 inhibitors, namely bomedemstat (bis tosylate salt) and pruro demstat (besylate salt), were similarly evaluated in a subset of these tumor cell lines (sNF96.2, sNF02.2, MOLM13, and NCIH510A).

[0121] Each experimental condition was tested in three technical replicates, including wells with medium only for background correction and normalization and vehicle - treated controls. After treatment, the cells were incubated at 37 °C in a humidified and controlled 5% CO 2 atmosphere (see Table 2 for the treatment period according to the growth curve of each cell line and the seeding cell number). When the drug incubation period exceeded 4 days, compound and medium refreshment was performed by adding 50 μl of medium supplemented with the 1 - fold concentrated compound at each corresponding dilution concentration (see Table 2). After treatment, cell viability was evaluated using either the MTT assay (Sigma - Aldrich) or AlamarBlue TM Cell Viability Reagent (Life Technologies) according to the manufacturer's instructions. The background was calculated as the average of the values of the medium - only controls and subtracted from each data point. The average of the background - corrected technical replicates was calculated and normalized by the average of the vehicle - treated controls (corresponding to 100% viability). The data were analyzed using GraphPad PRISM® version 9.0.1 (GraphPad Software, Inc., La Jolla, CA, USA), and the best - fit curve and EC 50Value (corresponding to the concentration of the compound at which 50% of the maximum effect is obtained; thus, the lower the EC 50 value, the stronger the potency) was calculated.

[0122] [Table 1]

[0123] [Table 2]

[0124] Results Using 15 NF1 mutant cell lines representing 10 different tumor types, the effect of the LSD1 inhibitor iadademstat on cell viability in various NF1 mutant tumors was evaluated.

[0125] LSD1 inhibitors such as iadademstat have been reported to exert a therapeutic effect not by killing cancer cells, but by inducing cancer cell differentiation and inhibiting cancer cell proliferation (Sacilotto N et al., ACS Pharmacol Transl Sci, 2021, 4(6):1818 - 34, doi:10.1021 / acsptsci.1c00223). In line with this, a decrease in tumor cell viability of more than 30% reflects a strong therapeutic effect of the corresponding LSD1 inhibitor. Therefore, in this experiment, the responses obtained after treatment with the LSD1 inhibitor were classified into the following three groups. (1) Strong response (survival rate decrease > 30%); (2) Moderate response (survival rate decrease > 15% and < 30% (more than 15% and less than 30%)); (3) Low response (survival rate decrease < 15%). Table 3 shows an overview of the classification according to the decrease in survival rate after treatment with the LSD1 inhibitor, together with the EC 50 values obtained for iadademstat.

[0126] [Table 3]

[0127] As shown in Table 3, 9 out of 15 tumor cell lines (60.0%) with NF1 mutations responded beneficially and favorably to LSD1 inhibitor treatment. Among these 9 cell lines, 7 (46.7%) showed a strong response to the LSD1 inhibitor iadademstat, and 2 (13.3%) showed a moderate response. Notably, all 9 cell lines that responded beneficially and favorably also showed sub-nanomolar EC 50 values for iadademstat (see Table 3), indicating that there is a clinically significant therapeutic effect even when administered at very low doses.

[0128] The effects of LSD1 inhibitors on the cell viability of NF1 mutant tumors were further tested using two additional LSD1 inhibitors, namely bomedemstat and pulrodemstat. Bomedemstat is an irreversible LSD1 inhibitor like iadademstat, while pulrodemstat is a reversible LSD1 inhibitor. Cell viability was evaluated in the sNF96.2 (MPNST), sNF02.2 (MPNST), MOLM13 (AML), and NCIH510A (SCLC) cell lines as described above (see Table 2). The results thus obtained, as presented in Table 4 (and Table 3 above for iadademstat), clearly show that all three LSD1 inhibitors, whether irreversible or reversible LSD1 inhibitors, are effective against NF1 mutant tumors.

[0129]

Table 4

[0130] Among the LSD1 inhibitors tested, iadademstat showed the highest potency (lowest EC 50 ) in all four NF1 mutant tumor cell lines. These results indicate that LSD1 inhibitors, including both irreversible LSD1 inhibitors (such as iadademstat and bomedemstat) and reversible LSD1 inhibitors (such as pulrodemstat), are beneficially effective for the treatment of NF1-mutant tumors for both germline and somatic NF1 mutations.

[0131] Although the invention has been described in connection with its specific embodiments, it will be understood that further modifications are possible, and that this patent or this patent application generally covers any variations, uses, or adaptations of the invention that follow the principles of the invention, and that departures from the disclosure herein that fall within the scope of known or customary practice in the art to which this invention pertains, and that are applicable to the essential features described herein, and that follow the appended claims.

Claims

1. A pharmaceutical composition for use in the treatment of NF1-mutated tumors, comprising an LSD1 inhibitor and one or more pharmaceutically acceptable excipients.

2. Use of LSD1 inhibitors for the manufacture of pharmaceutical compositions for the treatment of NF1-mutated tumors.

3. The pharmaceutical composition according to claim 1, wherein the LSD1 inhibitor is a small molecule.

4. The pharmaceutical composition according to claim 1, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, plurodemstat, bomedemstat, secridemstat, 1-((4-(methoxymethyl)-4-(((1R,2S)-2-phenylcyclopropylamino)methyl)piperidine-1-yl)methyl)cyclobutancarboxylic acid, 3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidine-1-yl)azetidine-1-sulfonamide, 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]phenyl]-2-fluorobenzonitrile, and pharmaceutically acceptable salts thereof.

5. The pharmaceutical composition according to claim 1, wherein the LSD1 inhibitor is selected from the group consisting of idademstat, prurodemstat, bomedemstat, and pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition according to claim 1, wherein the LSD1 inhibitor is idademstat or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, wherein the LSD1 inhibitor is idademstat dihydrochloride.

8. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1-mutated tumor is an NF1-mutated cancer.

9. NF1-mutated tumors include NF1-mutated leukemia, NF1-mutated lymphoma, NF1-mutated lung cancer, NF1-mutated breast cancer, NF1-mutated esophageal and gastric cancer, NF1-mutated esophageal cancer, NF1-mutated gastric cancer, NF1-mutated gastrointestinal cancer, NF1-mutated colorectal cancer, NF1-mutated liver cancer, NF1-mutated ovarian cancer, NF1-mutated uterine cancer, NF1-mutated cervical cancer, NF1-mutated pancreatic cancer, NF1-mutated prostate cancer, NF1-mutated bladder cancer, NF1-mutated pheochromocytoma, and NF1-mutated cephaloblastoma. A pharmaceutical composition according to any one of claims 1 or 3 to 7, selected from cervical cancer, NF1-mutated neuroblastoma, NF1-mutated gliablastoma, NF1-mutated optic tract glioma, NF1-mutated skin cancer, NF1-mutated malignant rhabdoid tumor, NF1-mutated rhabdomyosarcoma, NF1-mutated Ewing's sarcoma, NF1-mutated malignant peripheral nerve schwannoma, NF1-mutated plexiform neurofibroma, NF1-mutated gangliocytoma, NF1-mutated iris nodules, and NF1-mutated cutaneous neurofibroma.

10. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1-mutated tumor is NF1-mutated leukemia.

11. The pharmaceutical composition according to claim 10, wherein the NF1-mutated leukemia is NF1-mutated acute myeloid leukemia or NF1-mutated acute lymphoblastic leukemia.

12. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1-mutated tumor is NF1-mutated lung cancer.

13. The pharmaceutical composition according to claim 12, wherein the NF1-mutated lung cancer is NF1-mutated small cell lung cancer.

14. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1-mutated tumor is an NF1-mutated malignant rhabdoid tumor.

15. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1-mutated tumor is an NF1-mutated malignant peripheral nerve schwannoma.

16. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1 mutation tumor is an NF1 mutation plexiform neurofibroma.

17. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the NF1 mutant tumor has one or more inactivating mutations or inactivating gene changes affecting the NF1 gene.

18. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the pharmaceutical composition is administered to a subject having neurofibromatosis type 1.

19. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the pharmaceutical composition is administered to a subject who does not have neurofibromatosis type 1.

20. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the pharmaceutical composition is administered to a subject that is a human.

21. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the pharmaceutical composition is administered orally.

22. The pharmaceutical composition according to any one of claims 1 or 3 to 7, wherein the pharmaceutical composition is administered in combination with one or more further anticancer agents and / or in combination with radiotherapy.

23. The use according to claim 2, wherein the LSD1 inhibitor is selected from the group consisting of iademstat, prurodemstat, bomedemstat, and pharmaceutically acceptable salts thereof.

24. The use according to claim 2, wherein the LSD1 inhibitor is idademstat or a pharmaceutically acceptable salt thereof.

25. The use according to claim 2, wherein the LSD1 inhibitor is idademstat dihydrochloride.

26. NF1-mutated tumors include NF1-mutated leukemia, NF1-mutated lymphoma, NF1-mutated lung cancer, NF1-mutated breast cancer, NF1-mutated esophageal and gastric cancer, NF1-mutated esophageal cancer, NF1-mutated gastric cancer, NF1-mutated gastrointestinal cancer, NF1-mutated colorectal cancer, NF1-mutated liver cancer, NF1-mutated ovarian cancer, NF1-mutated uterine cancer, NF1-mutated cervical cancer, NF1-mutated pancreatic cancer, NF1-mutated prostate cancer, NF1-mutated bladder cancer, NF1-mutated pheochromocytoma, and NF1-mutated Use according to claim 2 or any one of claims 23 to 25, selected from head and neck cancer, NF1-mutated neuroblastoma, NF1-mutated gliablastoma, NF1-mutated optic tract glioma, NF1-mutated skin cancer, NF1-mutated malignant rhabdoid tumor, NF1-mutated rhabdomyosarcoma, NF1-mutated Ewing's sarcoma, NF1-mutated malignant peripheral nerve schwannoma, NF1-mutated plexiform neurofibroma, NF1-mutated gangliocytoma, NF1-mutated iris nodules, and NF1-mutated cutaneous neurofibroma.

27. ​​The use according to any one of claims 2 or 23 to 25, wherein the NF1 mutant tumor is NF1 mutant acute myeloid leukemia or NF1 mutant acute lymphoblastic leukemia.

28. The use according to any one of claims 2 or 23 to 25, wherein the NF1-mutated tumor is NF1-mutated small cell lung cancer.

29. A manufactured article for use in the treatment of NF1-mutated tumors, comprising an LSD1 inhibitor and one or more additional anticancer agents in the same or another pharmaceutical formulation.

30. - The LSD1 inhibitor is as defined in any one of claims 3 to 7; and / or - The NF1 mutant tumor is as defined in any one of claims 8 to 17; and / or - The subject to whom the manufactured article is administered is as defined in any one of claims 18 to 20; and / or - The manufactured product is administered orally. The manufactured article according to claim 29.