Methods and compositions for treating malignant peripheral nerve sheathing tumors

Abstract

The present disclosure relates to methods of treating cancer. The disclosure also relates to methods of treating cancer in an individual with a compound that is an inhibitor of the protein arginine N-methyltransferase 5 (PRMT5). More particularly, the present disclosure relates to the treatment of malignant peripheral nerve sheath tumor (MPNST).

Description

[0001] Background of this disclosure

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application No. 63 / 518,312, filed August 8, 2023, and U.S. Provisional Application No. 63 / 588,563, filed October 6, 2023, the disclosures of which are incorporated herein by reference in their entirety.

[0004] This disclosure of the field

[0005] This disclosure relates to methods of treating cancer. It also relates to treating an individual's cancer with a compound that is an inhibitor of protein arginine N-methyltransferase 5 (PRMT5). More specifically, this disclosure relates to treating malignant peripheral nerve sheath tumors (MPNST).

[0006] Description of related fields

[0007] PRMT5 is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the ω-nitro group of the L-arginine residue in a protein (ω-monomethylation), and catalyzes the transfer of a second methyl group to another ω-nitro group, producing symmetrical dimethylarginine (sDMA). PRMT5 forms a complex with methylsomal protein 50 (MEP50), which is essential for substrate recognition and orientation, and is also essential for the histone 2A and histone 4 methyltransferase activities catalyzed by PRMT5 (see, for example, Ho et al. (2013) PLoS ONE 8(2): e57008).

[0008] Homozygous deletions of p16 / CDKN2a are common in cancers, and these mutations often involve the co-deletion of adjacent genes, including the gene encoding methylthioadenosine phosphorylase (MTAP). It is estimated that approximately 15% of people with cancer have homozygous deletions of the MTAP gene (see, for example, Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754-13760).

[0009] Cells lacking MTAP activity exhibit elevated levels of the MTAP substrate methionine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity leads to decreased methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Therefore, loss of MTAP activity reduces PRMT5 methylation activity, thereby making cells selectively dependent on PRMT5 activity.

[0010] Malignant peripheral nerve schwannomas are cancerous forms of the connective tissue or sheath surrounding and protecting peripheral nerves. Malignant peripheral nerve schwannomas were previously named neurofibrosarcoma.

[0011] Malignant peripheral nerve sheath tumors (MPNSTs) can grow in any soft tissue of the body, such as muscles, fat, tendons, ligaments, lymph nodes and blood vessels, nerves, and other tissues that connect to and support the body. MPNSTs grow rapidly and can spread to other parts of the body.

[0012] Despite the importance of treating MPNST, effective therapies for this cancer remain elusive. Therefore, the development of new treatments for MPNST is still necessary.

[0013] Overview of this disclosure

[0014] One aspect of this disclosure provides a method for treating an individual with a malignant peripheral nerve schwannoma (MPNST). Such a method involves administering a therapeutically effective amount of a PRMT5 inhibitor to the individual.

[0015] In another aspect, this disclosure provides methods for reducing the size of an individual's malignant peripheral nerve sheath tumor (MPNST). Such methods include administering a therapeutically effective amount of a PRMT5 inhibitor to the individual.

[0016] These and other features and advantages of the invention will be more fully understood through the following detailed description in conjunction with the appended claims. It should be noted that the scope of the claims is defined by the detailed description therein, and not by the specific discussion of the features and advantages set forth in this specification.

[0017] Detailed description of this disclosure

[0018] Before describing the disclosed methods and materials, it should be understood that the aspects described herein are not limited to specific embodiments, and can certainly be modified accordingly. It should also be understood that the terminology used herein is for describing specific aspects only and is not intended to be restrictive unless specifically defined herein.

[0019] Based on this disclosure, those skilled in the art can conceive of the methods and compositions described herein to meet desired needs. This disclosure provides improvements in the treatment of cancer in an individual. As used herein, the terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals, and most preferably, humans.

[0020] Surprisingly, it has been found that administration of PRMT5 inhibitors, as disclosed in this article, can be used to treat malignant peripheral nerve schwannomas (MPNST).

[0021] The method described in this article can be used to treat a wide range of cancers, including tumors, including malignant peripheral nerve schwannomas (MPNST). This method involves administering a PRMT5 inhibitor to a patient or individual in need of such treatment.

[0022] As used herein, “PRMT5 inhibitor” means a compound as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of PRMT5, particularly in the presence of MTA in vitro or in vivo, or in cells in the presence of elevated levels of MTA. In some embodiments, the PRMT5 inhibitor is an MTA-co-PRMT5 inhibitor.

[0023] In some embodiments, the PRMT5 inhibitor disclosed herein is any of the PRMT5 inhibitors disclosed in published International Patent Application No. WO 2021 / 050915 A1, published on March 18, 2021, which is incorporated herein by reference in its entirety.

[0024] In some other embodiments, the PRMT5 inhibitor disclosed herein is any of the PRMT5 inhibitors disclosed in published International Patent Application No. WO / 2022 / 192745, published on September 15, 2022, which is incorporated herein by reference in its entirety.

[0025] For example, the PRMT5 inhibitor in the methods of this disclosure as described herein is a compound having the formula (IA), (IB), (IC), or (ID).

[0026] .

[0027] In one implementation, the PRMT5 inhibitor is a compound of the following formula:

[0028]

[0029] Or its pharmaceutically acceptable salt.

[0030] In another embodiment, the PRMT5 inhibitor is a compound of the following formula:

[0031]

[0032] Or its pharmaceutically acceptable salt.

[0033] In another embodiment, the PRMT5 inhibitor is a pharmaceutically acceptable salt of a compound of the following formula:

[0034] .

[0035] In another embodiment, the PRMT5 inhibitor is a compound of the following formula:

[0036] .

[0037] In other embodiments of the methods disclosed herein, the PRMT5 inhibitor is:

[0038] .

[0039] In some embodiments of the methods described herein, the PRMT5 inhibitor is:

[0040] .

[0041] In some embodiments of the methods described herein, the PRMT5 inhibitor is:

[0042] .

[0043] The PRMT5 inhibitor disclosed herein can be synthesized according to the methods described in published international patent application number WO 2021 / 050915 or published international application number WO / 2022 / 192745.

[0044] The PRMT5 inhibitors of this disclosure can be provided as pharmaceutical compositions comprising a therapeutically effective amount of such inhibitor and a pharmaceutically acceptable carrier, excipient, and / or diluent. The PRMT5 inhibitors of this disclosure can be prepared by any method known in the art and can be prepared for administration via any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal administration. In some embodiments, the PRMT5 inhibitors of this disclosure are administered intravenously in a hospital setting. In some other embodiments, administration may preferably be via an oral route.

[0045] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with biological systems (e.g., cells, cell cultures, tissues, or organisms) and does not interfere with the effectiveness of the bioactivity of the active ingredient. Therefore, in addition to inhibitors, the pharmaceutical compositions of this disclosure may also comprise diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0046] The PRMT5 inhibitors disclosed herein are administered in therapeutically effective amounts. As used herein, the terms "therapeutically effective amount" or "effective amount" refer to the amount of active agent that an investigator, physician, or other clinician seeks in a tissue, system, individual, or person to elicit a biological or pharmaceutical response. Typically, a therapeutically effective amount is sufficient to deliver a biological or pharmaceutical response to an individual without causing serious toxicity. The dosage of the active agent can range from 0.01 to 300 mg / kg / day, for example, 0.1 to 100 mg / kg / day, and more typically 0.5 to about 25 mg / kg of recipient body weight / day. Typical local dosage ranges are 0.01 to 3% wt / wt in a suitable carrier.

[0047] In some embodiments of the methods disclosed herein, the therapeutically effective dose of the PRMT5 inhibitor ranges from 0.01 to 300 mg / kg / day. For example, in some embodiments, the therapeutically effective dose of the PRMT5 inhibitor ranges from about 0.1 to 100 mg / kg / day, or 25 to 100 mg / kg / day, or 50 to 100 mg / kg / day.

[0048] In some implementations, the therapeutically effective amount of the PRMT5 inhibitor is less than 1% of the clinically established therapeutic amount (e.g., the amount required when the PRMT5 inhibitor is administered itself), such as less than 10%, less than 25%, or less than 50%.

[0049] PRMT5 inhibitors can also be administered in combination with other anticancer compounds or therapies. Combination therapy is intended to include administration of each active agent in a sequential, substantially simultaneous, or single dosage form. Each combination therapy is administered in a manner capable of providing the beneficial effects of the drug combination. Each compound of the combination therapy can be formulated as a separate composition such that the individual compositions can be administered sequentially or substantially simultaneously, for example, in a single dosage form having a fixed proportion of active agents or in multiple or separate dosage forms of each active agent. This disclosure is not limited to the order of administration: the PRMT5 inhibitors of this disclosure can be administered before or after the administration of other anticancer compounds (i.e., sequentially), or at the same time as the administration of other anticancer compounds (i.e., simultaneously).

[0050] The methods disclosed herein can be used as first-line treatment. Therefore, in some embodiments of the methods disclosed herein, the individual has not previously received any other first-line therapy.

[0051] The methods disclosed herein can also be used as first-line maintenance or second-line treatment. Therefore, in some embodiments of the methods disclosed herein, the individual has previously completed additional first-line therapy. For example, in some embodiments, the methods disclosed herein can provide a delay in cancer progression and recurrence in individuals who have previously completed additional first-line chemotherapy. For example, in some embodiments, the individual has previously completed platinum- and / or taxane-based chemotherapy (e.g., carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, etc.). In some embodiments of the methods disclosed herein, the individual has previously completed additional first-line chemotherapy and has a partial response to such chemotherapy.

[0052] Example

[0053] The following examples illustrate specific implementations of the methods of this disclosure and their various uses. They are for illustrative purposes only and should not be considered as limiting the scope of this disclosure.

[0054] Example 1: In vitro proliferation assay

[0055] Survival assays were performed using the MTAP-deficient human MPNST (malignant peripheral nerve sheath tumor) cell lines HS-PSS and sNF96.2. For this assay, on day 0, optimized cell numbers for each cell line were plated in 96-well plates and incubated overnight at 37°C + 5% CO2. On day 2, baseline CTG (CellTiter-Glo; Promega catalog number G7573) readings were collected from the designated wells, and the assay plates were treated with either DMSO (as a control) or a dose-response treatment of MRTX1719. Cells were then incubated at 37°C + 5% CO2 for 5 days. After this treatment period, CTG readings were collected. Using GraphPad PRISM software, the MRTX1719 relative survival IC50 for each cell line was calculated using the CTG values ​​at the end of treatment after baseline subtraction on day 0 for each cell line. 50 The results of these measurements are shown in Figures 1A and 1B, and the IC50 values ​​for each cell line are also shown. 50 As shown in Table 1.

[0056] Table 1.

[0057]

[0058] Example 2: In vivo tumor growth inhibition study

[0059] Immunocompromised nude mice were inoculated in the flank of their muscularly impaired regions with patient-derived tumor samples carrying MTAP deficiency. The tumors were inoculated when the average tumor volume reached approximately 90 mm². 3At age, mice were divided into two groups of five. The first group was given only the medium (0.5% methylcellulose (4000 cps) + 0.2% TWEEN80 in water). The second group was given a single active agent dose of MRTX1719 at a specified dose for the specified duration of treatment. The dosings used are reported in Table 2.

[0060] The tumor volume was measured with calipers every 2-3 days, and the tumor volume was calculated using the following formula: V=(0.5)a×b 2 Where a and b are the long and short vertical diameters of the tumor, respectively. The tumor growth inhibition (TGI) percentage is calculated using the following method:

[0061] %TGI = (1 - (mean final volume of treatment group - mean initial volume of treatment group) / (mean final volume of mediator group - mean initial volume of mediator group)) × 100

[0062] Tumor volume was measured over the 28 days of the study, and the mean tumor volume (mm) for each treatment group was also measured. 3 As shown in Table 2, MRTX1719 treatment for 28 days resulted in a 97% TGI.

[0063] Table 2.

[0064]

[0065] All experimental data management and reporting procedures were strictly performed in accordance with applicable standards and methods. Morbidity and mortality rates in animals were checked daily. During routine monitoring, the effects of tumor growth and treatment on behavior such as activity level, food and water consumption, weight gain / loss (measured twice weekly), and any other abnormalities were examined.

[0066] It should be understood that the embodiments and implementations described herein are for illustrative purposes only and will inspire those skilled in the art to make various modifications or changes based thereon, and such modifications and changes will be incorporated into the spirit and scope of this application and the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. A method of treating a malignant peripheral nerve sheath tumor in an individual, the method comprising administering to the individual a therapeutically effective amount of a protein arginine N-methyltransferase 5 (PRMT5) inhibitor, the inhibitor being a compound of Formula (IA), (IB), (IC), or (ID) 。 2. The method of claim 1, wherein the PRMT5 inhibitor is: or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the PRMT5 inhibitor is: or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the PRMT5 inhibitor is a pharmaceutically acceptable salt of a compound of the following formula: 。 5. The method of claim 1, wherein the PRMT5 inhibitor is a compound of the following formula: 。 6. A method of reducing the size of a malignant peripheral nerve sheath tumor in an individual, the method comprising administering to the individual a therapeutically effective amount of a protein arginine N-methyltransferase 5 (PRMT5) inhibitor, the inhibitor being a compound of Formula (IA), (IB), (IC), or (ID) 。 7. The method of claim 6, wherein the PRMT5 inhibitor is: or a pharmaceutically acceptable salt thereof.

8. The method of claim 6, wherein the PRMT5 inhibitor is: or a pharmaceutically acceptable salt thereof.

9. The method of claim 6, wherein the PRMT5 inhibitor is a pharmaceutically acceptable salt of a compound of the following formula: 。 10. The method of claim 6, wherein the PRMT5 inhibitor is a compound of the following formula: 。

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