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WO2025193927A1 - Utilisation d'un analogue de mithramycine pour le traitement du cancer - Google Patents

Utilisation d'un analogue de mithramycine pour le traitement du cancer

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Publication number
WO2025193927A1
WO2025193927A1 PCT/US2025/019734 US2025019734W WO2025193927A1 WO 2025193927 A1 WO2025193927 A1 WO 2025193927A1 US 2025019734 W US2025019734 W US 2025019734W WO 2025193927 A1 WO2025193927 A1 WO 2025193927A1
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WO
WIPO (PCT)
Prior art keywords
cancer
day
carcinoma
mutation
adenocarcinoma
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/019734
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English (en)
Inventor
Bradley PARRY
Aidan SOKOLOV
Keith FANDRICK
Brigette ROBERTS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
OrphAI Therapeutics Inc
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OrphAI Therapeutics Inc
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Application filed by OrphAI Therapeutics Inc filed Critical OrphAI Therapeutics Inc
Publication of WO2025193927A1 publication Critical patent/WO2025193927A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates generally to use of a mithramycin analogue and more specifically to the use of such analogues for the treatment of cancer.
  • chemotherapeutic drugs often reduce a cell’s ability to reproduce, or they kill cells that reproduce quickly.
  • First-generation chemotherapeutic drugs were designed from chemicals found to have highly toxic side effects, such as dyes or chemical warfare agents. The chemicals were then modified or used as discovered and harnessed for treating cancer. Over time, various classes of chemotherapeutic drugs have been developed, but despite the variety of available drugs, cancer often recurs after a period of remission, and some cancers are resistant to treatment.
  • Treatment of cancerous cells often requires repeated rounds of chemotherapy and can include radiation therapy or surgery as well.
  • Cells that are susceptible to one drug can develop resistance to the drug over time, requiring a change in therapy.
  • Combinations of drugs are also used, targeting multiple physiological pathways at once to treat the cancer. Because different chemotherapeutic agents target different physiological pathways, there is a constant need to find new chemicals that can target different types or stages of cancer.
  • SWItch/Sucrose Non-Fermentable Complex SWI/SNF
  • SWI/SNF complexes are found in eukaryotes, including both yeast and humans. These complexes are large multi-unit complexes that expose nucleic acid to a cell’s transcription/translation mechanisms through modification of the associations between nucleic acid and histones.
  • chromatin remodeling enzymes push and slide nucleosomes along DNA, and mutations in SWI/SNF are some of the most common mutations that make a cancer resistant to chemotherapy. Development of agents that can target such cancers is an ongoing challenge.
  • the SMARCA4 gene provides instructions for making a protein called BRG1, which forms one piece (subunit) of several different protein groupings called SWI/SNF protein complexes.
  • SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling.
  • Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged.
  • Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed.
  • the BRG1 protein uses a molecule called ATP to provide energy for chromatin remodeling, although the protein's specific role in remodeling is unclear.
  • the present invention relates to the use of a mithramycin analog, also known as EC-8042 or AIT-102, for the treatment of cancer.
  • the invention provides a compound of Formula (I),
  • Formula (I) or a salt, co-crystal or solvate thereof for the treatment of cancer in a subject See US 8,772,253, incorporated herein in its entirety; the compound of Formula (I) is also known as demycarosyl- 3D-P-D-ditioxosyl-mithramycin SK (DIG-MSK)).
  • the invention provides a method of treating cancer in a subject, comprising: a) analyzing the cancer for presence of a mutation or an alteration in level of expression of a gene or protein; b) determining that the cancer is sensitive to treatment based on the presence of the mutation or alteration in the level of expression of the gene or protein; and c) administering to the subject a compound of Formula (I),
  • the cancer is not a rhabdoid tumor, particularly when a SWI-SNF mutation is present in the cancer.
  • the mutation when present is selected from a SMARCA4 mutation, a SWI- SNF mutation, an ARID 1 A mutation, a SYT-SSX mutation, a MYC mutation, a SMARCA2/4 mutation, or a combination thereof.
  • the cancer is not a rhabdoid tumor, particularly when a SWI-SNF mutation is present in the cancer.
  • the composition is formulated as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • the cancer is selected from lung cancer, adenocarcinoma, non-small-cell lung cancer, hepatocellular carcinoma, primary hepatocellular carcinoma, renal medullary carcinoma, synovial carcinoma, ovarian cancer, pancreatic cancer, synovial sarcoma, osteosarcoma, squamous cell carcinoma, large-cell undifferentiated carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, endometrioid carcinoma, meningioma, adenocarcinomic, Ewing sarcoma, prostate cancer, colon cancer, small cell lung carcinoma (SCLC), renal carcinoma (ccRCC), epithelial cancer, breast cancer, epidermoid carcinoma, ovarian adenocarcinoma, colon adenocarcinoma, triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, human hepatocellular carcinoma (HCC), colorectal
  • the cancer is lung cancer, hepatocellular carcinoma, lung cancer, adenocarcinoma, lung carcinoma, lung adenocarcinoma, synovial sarcoma, endometrial cancer, ovarian cancer, pancreatic cancer, colorectal cancer, Ewing sarcoma, prostate cancer, colon cancer, small cell lung carcinoma (SCLC), renal carcinoma (ccRCC), epithelial cancer, breast cancer, epidermoid carcinoma, ovarian adenocarcinoma, colon adenocarcinoma, triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, human hepatocellular carcinoma (HCC), colorectal adenocarcinoma, renal cell carcinoma, thyroid carcinoma, endometrial adenocarcinoma, non-small cell lung cancer, metastatic gastrointestinal carcinoma, blader cancer, or synovial sarcoma.
  • SCLC small cell lung carcinoma
  • the cancer is a tumor.
  • the method further includes administering a chemotherapeutic agent.
  • the chemotherapeutic agent is administered simultaneously, separately, or sequentially to administration of the compound of Formula (I).
  • a dose of the composition is from 0.01 to 1000 mg/kg.
  • the dose is administered by oral, intravenous, intratumoral, subcutaneous, or intralesional routes.
  • the subject was previously treated with a chemotherapeutic agent.
  • the chemotherapy agent is altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5 -fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, a combination of trifluridine and tipiracil, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, or topotecan.
  • the level of expression of the gene or protein is increased or decreased relative to a subject not having cancer.
  • the mutation is a substitution, amplification, deletion, frameshift, point or insertion mutation.
  • the mutation is selected from a SMARCA4 mutation, a SWI-SNF mutation, a SYT-SSX mutation, a MYC mutation, an ARID 1 A mutation, a SMARCA2/4 mutation, or a combination thereof.
  • the mutation is a SWI-SNF mutation, the cancer is not a rhabdoid tumor.
  • FIG. 1 is a graph illustrating percent cell viability in a lung cancer line with a SMARCA4 mutation (A549 cells) treated with control or AIT- 102 (EC-8042).
  • FIG. 2 is a graph illustrating percent cell viability in a lung cancer line with a ARID 1 A mutation (SK-LU-1 cells) treated with control or AIT-102.
  • FIG. 3 is a graph illustrating percent cell viability in a hepatocellular carcinoma cell line with a SMARCA2/4 mutation (SNU398 cells) treated with control or AIT-102.
  • FIG. 4 is a graph illustrating percent cell viability in a synovial sarcoma cell line (HS- SY-II cells) treated with control or AIT- 102.
  • FIG. 5 is a graph illustrating percent cell viability in a non-cancerous cell line (Bud-8) treated with control or AIT- 102.
  • FIG. 6A-6H are graphs illustrating dose dependent percent cell survival curve of BUD8, A673, RL952, CAPAN2, HEK293, HS-SY-II, and hl299 cells.
  • FIG. 6A is a graph illustrating a dose dependent cell survival curve of BUD8 cells with AIT-102 treatment.
  • FIG. 6B is a graph illustrating dose dependent percent cell survival curve of A673 cells with AIT- 102 treatment.
  • FIG. 6C is a graph illustrating dose dependent percent cell survival curve of RL952 cells with AIT-102 treatment.
  • FIG. 6D is a graph illustrating dose dependent percent cell survival curve of A673 cells with CAPAN2 treatment.
  • FIG. 6E is a graph illustrating dose dependent percent cell survival curve of HEK cells with AIT - 102 treatment.
  • FIG. 6F is a graph illustrating dose dependent percent cell survival curve of HS-SY-II cells with AIT-102 treatment.
  • FIG. 6G is a graph illustrating dose dependent percent cell survival curve of hl299 cells with AIT-102 treatment.
  • FIG. 6H is a table illustrating concentration at 50 percent and maximum cell survival of BUD8, A673, RL952, CAPAN2, HEK293, HS-SY-II, and hl299 cells with AIT-102 treatment.
  • FIG. 7A-7D are graphs illustrating dose response curve of cisplatin and AIT- 102 in 22Rv-l, CCD-I8C0, DMS 79, and HCT 116 cells.
  • FIG. 7A is graph illustrating dose response curve of cisplatin and AIT- 102 in 22Rv-l cells.
  • FIG. 7B is graph illustrating dose response curve of cisplatin and AIT- 102 in CCD-I8C0 cells.
  • FIG. 7C is graph illustrating dose response curve of cisplatin and AIT-102 in DMS 79 cells.
  • FIG. 7D is graph illustrating dose response curve of cisplatin and AIT-102 in HCT 116 cells.
  • FIG. 8A-8D are graphs illustrating dose response curve of cisplatin and AIT- 102 in IMR- 90, KMRC-2, LS 1034, and NCI-H446 cells.
  • FIG. 8A is graph illustrating dose response curve of cisplatin and AIT- 102 in IMR-90 cells.
  • FIG. 8B is graph illustrating dose response curve of cisplatin and AIT- 102 in KMRC-2 cells.
  • FIG. 8C is graph illustrating dose response curve of cisplatin and AIT- 102 in LS 1034 cells.
  • FIG. 8D is graph illustrating dose response curve of cisplatin and AIT-102in NCI-H446 cells.
  • FIG. 9A-9D are graphs illustrating dose response curve of cisplatin and AIT-102in NCI- H522, PC-3, A549, and CAL-51 cells.
  • FIG. 9A is graph illustrating dose response curve of cisplatin and AIT-102 in NCI-H522 cells.
  • FIG. 9B is graph illustrating dose response curve of cisplatin and AIT- 102 in PC-3 cells.
  • FIG. 9C is graph illustrating dose response curve of cisplatin and AIT- 102 in A549 cells.
  • FIG. 9D is graph illustrating dose response curve of cisplatin and AIT- 102 in CAL-51 cells.
  • FIG. 10A-10D are graphs illustrating dose response curve of cisplatin and AIT- 102 in Calu-1, Calu-3, EFO-27, and GP2d cells.
  • FIG. 10A is graph illustrating dose response curve of cisplatin and AIT-102in Calu-lcells.
  • FIG. 10B is graph illustrating dose response curve of cisplatin and AIT-102 in Calu-3 cells.
  • FIG. 10C is graph illustrating dose response curve of cisplatin and AIT-102 in EFO-27 cells.
  • FIG. 10D is graph illustrating dose response curve of cisplatin and AIT- 102 in GP2d cells.
  • FIG. 11A-11D are graphs illustrating dose response curve of cisplatin and AIT- 102 in HCC 1806, Hs 766T, HT-55, and HuP-T4 cells.
  • FIG. 11A is graph illustrating dose response curve of cisplatin and AIT- 102 in HCC 1806 cells.
  • FIG. 11B is graph illustrating dose response curve of cisplatin and AIT- 102 in Hs 766T cells.
  • FIG. 11C is graph illustrating dose response curve of cisplatin and AIT-102 in HT-55 cells.
  • FIG. 11D is graph illustrating dose response curve of cisplatin and AIT-102 in HuP-T4 cells.
  • FIG. 11A is graph illustrating dose response curve of cisplatin and AIT- 102 in HCC 1806, Hs 766T, HT-55, and HuP-T4 cells.
  • FIG. 11A is graph illustrating dose response curve of cisplatin and AIT- 102 in H
  • FIGS. 12A-12D are graphs illustrating dose response curve of cisplatin and AIT- 102 in JHH-5, NCI-H1437, NCI-H1563, and RL95-2 cells.
  • FIG. 12A is graph illustrating dose response curve of cisplatin and AIT- 102 in JHH-5 cells.
  • FIG. 12B is graph illustrating dose response curve of cisplatin and AIT-102 in NCI-H1437 cells.
  • FIG. 12C is graph illustrating dose response curve of cisplatin and AIT-102 in NCI-H1563 cells.
  • FIG. 12D is graph illustrating dose response curve of cisplatin and AIT-102 in RL95-2 cells.
  • FIG. 13A-13D are graphs illustrating dose response curve of cisplatin and AIT- 102 in SK-HEP-1, SK-LU-1, SNU-387, and SNU-423 cells.
  • FIG. 13A is graph illustrating dose response curve of cisplatin and AIT- 102 in SK-HEP-1 cells.
  • FIG. 13B is graph illustrating dose response curve of cisplatin and AIT- 102 in SK-LU-1 cells.
  • FIG. 13C is graph illustrating dose response curve of cisplatin and AIT-102 in SNU-387 cells.
  • FIG. 13D is graph illustrating dose response curve of cisplatin and AIT- 102 in SNU-423 cells.
  • FIG. 14A-14D are graphs illustrating dose response curve of cisplatin and AIT- 102 in SW-1417, SW-156, SW-48, and TOV-112D cells.
  • FIG. 14A is graph illustrating dose response curve of cisplatin and AIT-102 in SW-1417 cells.
  • FIG. 14B is graph illustrating dose response curve of cisplatin and AIT-102 in SW-156 cells.
  • FIG. 14C is graph illustrating dose response curve of cisplatin and AIT-102 in SW-48 cells.
  • FIG. 14D is graph illustrating dose response curve of cisplatin and AIT-102 in TOV-112D cells.
  • FIG. 15A-15D are graphs illustrating dose response curve of cisplatin and AIT- 102 in 786-0, 8305 C, Caki-1, and DU 145 cells.
  • FIG. 15A is graph illustrating dose response curve of cisplatin and AIT-102 in 786-0 cells.
  • FIG. 15B is graph illustrating dose response curve of cisplatin and AIT-102 in 8305 C cells.
  • FIG. 15C is graph illustrating dose response curve of cisplatin and AIT-102 in Caki-1 cells.
  • FIG. 15D is graph illustrating dose response curve of cisplatin and AIT- 102 in DU 145 cells.
  • FIG. 16A-16D are graphs illustrating dose response curve of cisplatin and AIT- 102 in HEC-l-A, HEC-265, HT-29, and IHH-4 cells.
  • FIG. 16A is graph illustrating dose response curve of cisplatin and AIT- 102 in HEC-l-A cells.
  • FIG. 16B is graph illustrating dose response curve of cisplatin and AIT-102 in HEC-265 cells.
  • FIG. 16C is graph illustrating dose response curve of cisplatin and AIT-102 in HT-29 cells.
  • FIG. 16D is graph illustrating dose response curve of cisplatin and AIT- 102 in IHH-4 cells.
  • FIG. 17A-17D are graphs illustrating dose response curve of cisplatin and AIT- 102 in JHH-6, KP4, NCI-H1993, and NCI-H2081 cells.
  • FIG. 17A is graph illustrating dose response curve of cisplatin and AIT-102 in JHH-6 cells.
  • FIG. 17B is graph illustrating dose response curve of cisplatin and AIT-102 in KP4 cells.
  • FIG. 17C is graph illustrating dose response curve of cisplatin and AIT-102 in NCI-H1993 cells.
  • FIG. 17D is graph illustrating dose response curve of cisplatin and AIT- 102 in NCI-H2081 cells.
  • FIG. 18A-18D are graphs illustrating dose response curve of cisplatin and AIT- 102 in NCI-H2286, OVCAR-4, OVCAR-5, and RT4 cells.
  • FIG. 18A is graph illustrating dose response curve of cisplatin and AIT-102 in NCI-H2286 cells.
  • FIG. 18B is graph illustrating dose response curve of cisplatin and AIT-102 in OVCAR-4 cells.
  • FIG. 18C is graph illustrating dose response curve of cisplatin and AIT-102 in OVCAR-5 cells.
  • FIG. 18D is graph illustrating dose response curve of cisplatin and AIT- 102 in RT4 cells.
  • FIG. 19A-19B are graphs illustrating dose response curve of cisplatin and AIT-102 in NCI-H1869 and SUM 159PT cells.
  • FIG. 19A is graph illustrating dose response curve of cisplatin and AIT-102 in NCI-H1869 cells.
  • FIG. 19B is graph illustrating dose response curve of cisplatin and AIT- 102 in SUM 159PT cells.
  • the term “beneficial effect” or “efficacious” refers to an improvement of symptoms of a disease, reduction in detrimental symptoms, improvement of clinical test results, reduction in pain, improvement of quality of life, or other desirable results.
  • Administration refers to providing the composition of the disclosure in a therapeutically effective amount to the subject in need of treatment.
  • Administration routes include but are not limited to intracutaneous, subcutaneous, intravenous, intralesional, intratumoral, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal, oral, sublingual buccal, rectal, vaginal, nasal ocular administrations, as well infusion, inhalation, and nebulization.
  • administration is in combination with one or more additional therapy.
  • chemotherapeutic agent for example, immunomodulating agents, altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5- fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, a combination of trifluridine and tipiracil, vincristine, vinblastine, vinorelbine
  • a chemotherapeutic agent for example, immunomodulating agents, altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarba
  • treatment refers to an approach or regimen designed to improve or alleviate symptoms of a disease, sickness, or infirmity. Treatment can lead to reduction in pain, improvement of quality of life, or decrease in size, number, or distribution of a tumor, cancer, or cancerous cells.
  • treatment of a cancer results in tumor shrinkage or a reduction in the number of cancer cells.
  • Treatment of cancer also occurs when symptoms or tests for cancer or cancerous cells are improved, or when symptoms or tests for cancer or cancerous cells do not worsen or stabilize. Failure of treatment occurs in some aspects, when a tumor metastasizes, grows in size, does not shrink, or when cancer cells increase in number.
  • the present methods are used after a cancer has been treated with a chemotherapy agent and treatment has failed.
  • Treatments for cancer referred to herein include chemotherapy, corticosteroids, an immunomodulating agent, a proteasome inhibitor, a histone deacetylase (HDCA) inhibitor, immunotherapy, a nuclear export inhibitor, stem cell transplant, radiation therapy, surgery, and any combination thereof.
  • Surgical treatments include, for example, cryosurgery, electrosurgery, laser surgery, Mohs surgery, laparoscopic surgery, segmentectomy, resection, lobectomy, robotic surgery, and chemical ablation.
  • Radiation treatments include, for example, 3D conformal radiation therapy (3DCRT), image guided radiation therapy (IGRT), intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), brachytherapy, intraoperative radiation therapy (IORT), stereotactic radiosurgery (SRS), proton therapy, and stereotactic body radiation therapy (SBRT).
  • 3DCRT 3D conformal radiation therapy
  • IGRT image guided radiation therapy
  • IMRT intensity modulated radiation therapy
  • VMAT volumetric modulated arc therapy
  • brachytherapy brachytherapy
  • intraoperative radiation therapy IORT
  • stereotactic radiosurgery SRS
  • proton therapy proton therapy
  • SBRT stereotactic body radiation therapy
  • chemotherapy refers to any therapeutic agent used to treat cancer.
  • a chemotherapeutic agent includes any substance or agent having a toxic effect on cells resulting in cell death or reduced proliferation.
  • Chemotherapy targets cells at various cell cycle stages to inhibit or disrupt cell reproduction and proliferation.
  • Chemotherapeutic agents include cell-cycle nonspecific agents and cell-cycle specific agents.
  • Chemotherapy that is used for the treatment of cancers described herein includes, for example, altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5 -fluorouracil, 6-mercap topurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, or topotecan.
  • Immunomodulating agents include checkpoint inhibitors, for example, anti-PDl or anti- CTLA4 inhibitors.
  • Illustrative examples include pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, relatlimab, or a combination thereof.
  • SWI/SNF is a tumor suppressor in a number of diverse malignancies.
  • subunits of the mammalian complex including SMARCB1, PBRM1, SMARCB1, SMARCA4, and ARID2, are frequently mutated in human cancers.
  • F(l) was effective in reducing the number of viable cancer cells with such mutations in at least lung cancer, synovial sarcoma, and hepatocellular carcinoma.
  • Synovial sarcoma is an aggressive malignant tumor that originates in mesenchymal tissue.
  • SS is usually associated with mutations that create a translocation of a synaptotagmin (SYT) gene on chromosome 18 to an SSX gene that is involved in synovial sarcomas on chromosome X.
  • This translocation forms a SYT-SSX fusion transcript, thought to function as an aberrant transcriptional regulator.
  • SS synaptotagmin
  • F(l) was found to significant decrease viability in HS-SY-II cells, which is a large step forward in cancer treatment for SS.
  • the invention provides a method of treating cancer in a subject including administering to the subject a compound of Formula (I),
  • Formula (I) or a salt, co-crystal or solvate thereof for the treatment of cancer in a subject is with the proviso that the cancer is not a rhabdoid tumor.
  • the invention provides a method of treating cancer in a subject, comprising: a) analyzing the cancer for presence of a mutation or an alteration in level of expression of a gene or protein; b) determining that the cancer is sensitive to treatment based on the presence of the mutation or alteration in the level of expression of the gene or protein; and c) administering to the subject a compound of Formula (I), Formula (I) or a salt, co-crystal or solvate thereof.
  • treatment of cancer is with the proviso that the cancer is not a rhabdoid tumor when a mutation in the cancer is a SWI-SNF mutation.
  • Exemplary cancers include but are not limited to Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adenocarcinoma, Ewing Sarcoma, Small Cell Lung Carcinoma (SCLC), Renal Carcinoma (ccRCC), Epidermoid Carcinoma, Ovarian Adenocarcinoma, Colon Adenocarcinoma, Triple-Negative Breast Cancer (TNBC), Pancreatic Ductal Adenocarcinoma (PDAC), Human Hepatocellular Carcinoma (HCC), Colorectal Adenocarcinoma, Renal Cell Carcinoma, Thyroid Carcinoma, Endometrial Adenocarcinoma, Metastatic Gastrointestinal Carcinoma, Blader Cancer, Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Rel
  • said composition is a pharmaceutical composition.
  • the compound of Formula (I) is also known as demycarosyl-3D-3-D-digitoxosyl- mithramycin SK and is referred to herein as F(l).
  • the compound of Formula (I) is a salt, a hydrochloride salt, a phosphate salt, a sulfate salt, a mesylate salt, a sodium salt, a citrate salt, a tartrate salt, a succinate sat, a hydrobromide salt, a glutamate salt, or a malate salt.
  • the compound of Formula (I) may be obtained from genetically modified bacteria by combinatorial biosynthesis, specifically by fermentation of Streptomyces argillaceus M3Wl-pMP*3BII (J. Med. Chem. (2012) 55:5813 - 5825).
  • the compound of Formula (I) is currently under development as antitumor agent due to the fact that it inhibits replication and transcription processes during macromolecular biosynthesis, by virtue of its affinity towards GC-rich DNA regions located at the minor groove of DNA, especially the site of union of the Spl transcription factor.
  • proteins whose expression is affected by this drug include various protooncogenes, proteins involved in angiogenesis or antiapoptotic processes, p53-mediated transcriptional responses, as well as multidrug resistant gene 1 (MDR-1).
  • the compound of Formula (I) is 10 times less toxic than mithramycin in vivo, and therefore has a greater therapeutic window while it is active both in vitro and in cancer xenograft models.
  • the compound of Formula (I) is disclosed in US Patent No. 8,772,253 and US Patent No. 10,568,899, the contents of which are incorporated herein by reference in their entirety.
  • the pharmaceutical composition may also contain other therapeutic agents, and may be formulated, for example, by employing conventional vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, preservatives, etc.) according to techniques known in the art of pharmaceutical formulation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the Formula (I).
  • the composition of the present invention is a pharmaceutical composition and comprises an excipient and/or carrier, wherein the excipient and/or carrier is selected from a diluent, bulking agent, filler, anti-adherent, binder, coating, colour, disintegrant, flavour, glidant, lubricant, preservative, sorbent, sweetener, or vehicle.
  • a composition can be in crystalline, powder, granular, compacted solid, liquid, solution, suspension, elixir, syrup, emulsion, cream, gel, droplet, mist, vapor, or spray form.
  • compositions disclosed herein are formulated with additional agents that promote entry into the desired cell or tissue.
  • additional agents include micelles, liposomes, and dendrimers.
  • the term "pharmaceutically acceptable” refers to the fact that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the carrier, diluent, or excipient or composition thereof may be administered to a subject along with a conjugate of the invention without causing any undesirable biological effects or interacting in an undesirable manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the composition includes pharmaceutically acceptable carriers, excipients, or stabilizers.
  • the carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3 -pentanol, and m-cresol); low molecular weight peptides (less than about 10 amino acid residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as poly(ethylene glycol)-2-gly
  • Examples of a carrier include, but are not limited to, liposome, nanoparticles, ointment, micelles, microsphere, microparticle, cream, emulsion, and gel.
  • excipients include, but are not limited to, anti-adherents such as magnesium stearate, binders such as saccharides and their derivatives (sucrose, lactose, starches, cellulose, sugar alcohols and the like) protein like gelatin and synthetic polymers, lubricants such as talc and silica, and preservatives such as antioxidants, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium sulfate and parabens.
  • anti-adherents such as magnesium stearate
  • binders such as saccharides and their derivatives (sucrose, lactose, starches, cellulose, sugar alcohols and the like) protein like gelatin and synthetic polymers
  • diluents include, but are not limited to, water, alcohol, saline solution, glycol, mineral oil, and dimethyl sulfoxide (DMSO).
  • the pharmaceutical compositions include one or more additional therapeutically or biologically active substances.
  • the present invention also relates to a composition, according to any of the foregoing, for use as a medicament. Furthermore, the present invention also relates to a composition, according to any of the foregoing, for use in the prevention and/or treatment of cancer in a subject.
  • the cancer is a disease or disorder of uncontrolled cellular proliferation.
  • the present invention also relates to the use of a composition, according to any of the foregoing, in the manufacture of a medicament for the prevention and/or treatment of lung cancer, synovial cancer or hepatocellular carcinoma.
  • the present invention also relates to a method of treatment of a subject using a composition, according to any of the foregoing.
  • the method is a method of treatment of lung cancer, adenocarcinoma, non-small-cell lung cancer, hepatocellular carcinoma, primary hepatocellular carcinoma, renal medullary carcinoma, synovial carcinoma, adenocarcinoma, lung carcinoma, lung adenocarcinoma, endometrial cancer, Ewing sarcoma, prostate cancer, colon cancer, small cell lung carcinoma (SCLC), renal carcinoma (ccRCC), epithelial cancer, breast cancer, epidermoid carcinoma, ovarian adenocarcinoma, colon adenocarcinoma, triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, human hepatocellular carcinoma (HCC), colorectal adenocarcinoma, renal cell carcinoma, thyroid carcinoma, endometrial adenocarcinoma, non-small cell lung cancer, metastatic gastrointestinal carcinoma, blader cancer, ovarian cancer, pan
  • the lung cancer is a non-small cell lung cancer (NSCLC).
  • the bladder cancer is a bladder urothelial (transitional cell) carcinoma.
  • the melanoma is a skin melanoma.
  • the kidney cancer is a kidney urothelial carcinoma.
  • the colorectal cancer is a colon adenocarcinoma.
  • the head and neck cancer is a head and neck squamous cell carcinoma (HNSCC).
  • the cancer is a lung cancer, hepatocellular carcinoma, or synovial sarcoma.
  • the cancer is a tumor. Such a diagnosis may be made clinically.
  • the compound is administered via intracutaneous, subcutaneous, intravenous, intratumoral, intralesional, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal, oral, sublingual buccal, rectal, vaginal, nasal ocular administrations, as well infusion, inhalation, and nebulization routes.
  • the method further includes administering a chemotherapeutic agent.
  • the chemotherapeutic agent is administered simultaneously, separately, or sequentially to administration of the compound of Formula (I).
  • the subject was previously treated with a chemotherapeutic agent.
  • the chemotherapy agent is altretamine, busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, trabectedin, 5 -fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, tipiracil, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, or topotecan.
  • an effective amount of an active agent refers an amount that is non-toxic to a subject or a majority or normal cells but is an amount of the active agent that is sufficient to provide a desired effect (e.g., treatment of a skeletal muscle disorder, metabolic disorder, blood disorder, or cancer). This amount may vary from subject to subject, depending on the species, age, and physical condition of the subject, the severity of the disease that is being treated, the particular conjugate, or more specifically, the particular active agent used, its mode of administration, and the like. Therefore, a suitable effective amount may be determined by one of ordinary skill in the art.
  • the composition of the present invention may be administered between 0.01 and 1000 mg/kg bodyweight/dose, between 0.1 and 200 mg/kg bodyweight/dose, more between 1 and 10 mg/kg bodyweight/dose.
  • Said dose may be administered (i) in a single daily dose, (ii) divided into n smaller doses which are administered at n intervals throughout the day, whereby n is a number between 2 and 5, between 2 and 3, or (iii) accumulated form days, whereby said accumulated dose is administered once every m days, whereby m is an interval of between 2 and 7 days, or between 3 and 5 days.
  • the therapeutically effective amount of the composition of the present invention is about 0.5 mg/kg/day, about 1 mg/kg/day, about 5 mg/kg/day, about 10 mg/kg/day, about 15 mg/kg/day, about 20 mg/kg/day, about 25 mg/kg/day, about 30 mg/kg/day, about 40 mg/kg/day, about 50 mg/kg/day, about 60 mg/kg/day, about 70 mg/kg/day, about 80 mg/kg/day, about 90 mg/kg/day, about 100 mg/kg/day, about 110 mg/kg/day, or about 125 mg/kg/day. In a particular aspect, the therapeutically effective amount of the composition of the present invention is about 25 mg/kg/day.
  • the therapeutically effective dose of the composition is greater than 250 mg/kg/day, for example between about 250 mg/kg/day and 1 g/kg/day. In some aspects, the therapeutically effective amount of the composition is about 1 mg/kg/day, about 5 mg/kg/day, about 10 mg/kg/day, about 15 mg/kg/day, about 20 mg/kg/day, about 25 mg/kg/day, about 30 mg/kg/day, about 40 mg/kg/day, about 50 mg/kg/day, about 60 mg/kg/day, about 70 mg/kg/day, about 80 mg/kg/day, about 90 mg/kg/day, about 100 mg/kg/day, about 110 mg/kg/day, about 120 mg/kg/day, about 130 mg/kg/day, about 140 mg/kg/day, about 150 mg/kg/day, about 160 mg/kg/day, about 170 mg/kg/day, about 180 mg/kg/day, about 190 mg/kg/day, about 200 mg/kg/day, about 210 mg/kg/day, about
  • subject refers to a human or other animal, including rodents, ungulates, or mammals; for example, horses, cattle, sheep, pigs, goats, llama, camel, dogs, cats, birds, ferrets, rabbits, squirrels, mice, rats, or ferrets.
  • the subject is a human subject.
  • the level of expression of the gene or protein is increased or decreased relative to a subject not having cancer.
  • expression of the gene or protein may be increased by at least 0.5 times greater than expression of expression of the gene or protein of a subject not suffering from cancer.
  • Expression of the gene or protein may be increased by at least
  • expression or level of the gene or protein may be increased or decreased by at least about 2.5% to about 99% or more, e.g., about 2.5%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, relative to corresponding expression or level of the gene or protein in a subject not suffering from cancer.
  • the mutation is a substitution, amplification, deletion, frameshift, point or insertion mutation.
  • mutation refers to any alteration in the nucleotide sequence of a nucleic acid molecule, which can result in changes to the corresponding amino acid sequence of a protein.
  • these alterations can include substitutions, amplification, deletions, insertions, frameshift, point mutation, or inversions of one or more nucleotides. Mutations may occur naturally through errors in DNA replication or be induced by external factors such as chemical agents, radiation, or genetic engineering techniques. The resulting nucleic acid sequences and proteins may exhibit modified functional properties.
  • amplification refers to refers to an increase in the number of copies of a specific nucleotide sequence within a genome. This type of mutation can result in the overexpression of the corresponding gene, leading to an elevated production of the associated protein. Amplification mutations can occur naturally or be induced by external factors like chemical agents or radiation. The increased gene dosage resulting from amplification mutations can have significant effects on cellular function and phenotype, which are relevant to the applications described herein.
  • deletion refers to the removal of one or more nucleotides from a nucleic acid sequence. This type of mutation can result in the loss of genetic material, potentially leading to a frameshift if the number of nucleotides deleted is not a multiple of three. Deletion mutations can disrupt the reading frame of the gene, often resulting in the production of a nonfunctional protein or the complete absence of the protein. These mutations can occur naturally due or be induced by external factors such as chemical agents or radiation. The effects of deletion mutations on gene function and protein expression are considered in the context of the applications described herein.
  • frameshift refers to when nucleotides are inserted into or deleted from a nucleic acid sequence in numbers that are not multiples of three. This type of mutation shifts the reading frame of the gene, altering the triplet codon sequence downstream of the mutation site. As a result, the encoded protein is typically rendered nonfunctional due to the production of an aberrant amino acid sequence and premature stop codons. Frameshift mutations can arise naturally from errors in DNA replication or be induced by external factors such as chemical agents or radiation. The impact of frameshift mutations on gene function and protein synthesis is considered in the context of the applications described herein.
  • point mutation refers to a change in a single nucleotide within a nucleic acid sequence. This type of mutation can result in the substitution of one base pair for another, potentially altering the amino acid sequence of the encoded protein. Point mutations can be classified as silent, missense, or nonsense mutations, depending on their effect on the protein's function. These mutations can occur naturally due or be induced by external factors such as chemical agents or radiation. The consequences of point mutations on gene expression and protein function are considered in the context of the applications described herein.
  • Insertion refers to the addition of one or more nucleotides into a nucleic acid sequence. Insertion mutation can disrupt the reading frame of the gene if the number of inserted nucleotides is not a multiple of three, potentially leading to a frameshift mutation. Insertion mutations can alter the amino acid sequence of the encoded protein, often resulting in a nonfunctional or altered protein. Insertion mutations can occur naturally or be induced by external factors such as chemical agents or radiation. The effects of insertion mutations on gene function and protein expression are considered in the context of the applications described herein.
  • the mutation is selected from a SMARCA4 mutation, a SWI-SNF mutation, a SYT-SSX mutation, a MYC mutation, an ARID 1 A mutation, a SMARCA2/4 mutation, or a combination thereof.
  • Other mutations will be known to those of skill in the art.
  • the cancer when the cancer includes a SWI-SNF mutation, the cancer is one that is not a rhabdoid tumor.
  • a “SMARCA4” or “BRG1” gene refers to a gene that encodes a protein involved in chromatin remodeling, which is crucial for regulating the binding of transcription factors to DNA.
  • the SMARCA4 protein is a key component of the SWI/SNF complex, playing a significant role in gene expression, DNA repair, and cell cycle control. Mutations or alterations in SMARCA4 are associated with various cancers and developmental disorders, highlighting its importance as a tumor suppressor gene. The functional implications of SMARCA4 in cellular processes and its potential therapeutic applications are considered in the context of the disclosure described herein.
  • SWI-SNF or “SWItch/Sucrose Non-Fermentable” refers to a subfamily of ATP- dependent chromatin remodeling complexes found in eukaryotes. These complexes play a crucial role in regulating gene expression by altering the structure of chromatin, thereby facilitating or hindering the access of transcription factors to DNA.
  • the SWI-SNF complex utilizes energy from ATP hydrolysis to reposition nucleosomes, which are the basic units of chromatin, enabling the activation or repression of specific genes. Mutations or dysregulation of SWI-SNF components have been linked to various cancers and developmental disorders, underscoring its importance in maintaining genomic integrity and cellular function.
  • SYT-SSX refers to a fusion gene resulting from the chromosomal translocation t(X;18)(pl 1.2;ql 1.2), commonly found in synovial sarcomas. This translocation fuses the SYT gene on chromosome with one of the SSX genes (SSX1, SSX2, or SSX4) on the X chromosome, creating a chimeric gene that encodes the SYT-SSX fusion protein.
  • the SYT-SSX protein combines the transcriptional activation domain of SYT with the transcriptional repression domain of SSX, leading to aberrant gene expression.
  • This fusion protein is implicated in the malignant transformation and proliferation of synovial sarcoma cells by affecting critical pathways such as cyclin DI expression.
  • the role of SYT-SSX in oncogenesis and its potential as a therapeutic target are considered in the context of the applications described herein.
  • MYC refers to a proto-oncogene that encodes a transcription factor involved in the regulation of various cellular processes, including cell growth, proliferation, and apoptosis.
  • the MYC gene family includes c-MYC, L-MYC, and N-MYC, each playing critical roles in normal cellular function and development. Aberrations in MYC expression or function, such as overexpression or mutations, are implicated in the pathogenesis of numerous cancers, including Burkitt lymphoma and various carcinomas.
  • the MYC protein influences gene expression by binding to specific DNA sequences, thereby regulating the transcription of target genes.
  • ARID 1 A or “AT -rich interaction domain-containing protein 1A” refers to a gene that encodes a protein involved in chromatin remodeling, which is essential for regulating gene expression.
  • the ARID 1 A protein is a key subunit of the SWI/SNF complex, which modulates the structure of chromatin to facilitate or inhibit the access of transcription factors to DNA. Mutations or alterations in ARID 1 A are frequently observed in various cancers, including ovarian, endometrial, and gastric cancers, where they often lead to loss of function and contribute to tumorigenesis.
  • SMARCA2/4 refers to genes that encode proteins belonging to the SWI/SNF family of chromatin remodeling complexes.
  • BRM Brahma
  • BRG1 Brahma-related gene 1
  • SMARCA2 and SMARCA4 possess ATPase activity, which provides the energy required for chromatin remodeling. Mutations or alterations in these genes are associated with various cancers and developmental disorders, highlighting their importance in maintaining genomic stability and proper cellular function.
  • AIT- 102 was diluted to a working concentration in the appropriate media based on the cell line, and cells were seeded in 96 well plates. Next, AIT-102 was added to the wells at the indicated concentration. Viability assays were performed for 72 hours following manufacturer instructions (CyQUANT XTT Cell Viability Assay, Invitrogen; X12223). AIT-102 was added to tested wells after seeding at the above stated concentration for 44 hours. Next, fresh media and drug was added, and the XTT reagent was added to wells. At 48 hours and 72 hours post-seeding, the plate was read at 450 nm and 660 nm using a VICTOR NivoTM plate reader.
  • Survival (%) (LumTest article-LumMedium control) / (LumNone treated-LumMedium control) > ⁇ 100%.
  • a cell line with a SYT-SSX fusion transcript (HS-SY-II) was surprisingly susceptible to treatment with F(l) as well, with less than 20% of cells viable after treatment (see FIG. 4).
  • a cell line with a SYT-SSX fusion transcript (HS-SY-II) was surprisingly susceptible to treatment with F(l) as well, with less than 20% of cells viable after treatment (see FIG. 4).
  • There was a significant decrease in percent viability of RL95-2 cells, endometrial cancer cells, treated with F(l) compared to a control treatment see FIG. 8C.
  • Viability of Capan-2 cells pancreatic cancer cells, treated with F(l) was decreased compared to a control treatment (see FIG. 8D).
  • Viability of Bud-8 cells noncancerous cells, treated with F(l) was decreased compared to a control treatment (see FIG. 5).

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Abstract

La présente invention divulgue une méthode de traitement du cancer chez un sujet par administration d'une composition pharmaceutique comprenant un composé de formule (I) ou son sel, co-cristal ou solvate. La méthode divulguée offre une approche prometteuse pour traiter des cancers, y compris des cancers récalcitrants, et contribue ainsi favorablement au domaine de l'oncologie.
PCT/US2025/019734 2024-03-14 2025-03-13 Utilisation d'un analogue de mithramycine pour le traitement du cancer Pending WO2025193927A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120270823A1 (en) * 2009-07-23 2012-10-25 Entrechem, S.L. Aureolic acid derivatives, the method for preparation thereof and the uses thereof
US20190350951A1 (en) * 2015-09-17 2019-11-21 Entrechem, S.L. Combinations of a mithramycin analogue and another chemotherapeutic agent for the treatment of triple negative breast cancer
US20210155932A1 (en) * 2017-07-21 2021-05-27 Novartis Ag Compositions and methods to treat cancer
US20220296622A1 (en) * 2019-09-16 2022-09-22 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of swi-snf mutant tumors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120270823A1 (en) * 2009-07-23 2012-10-25 Entrechem, S.L. Aureolic acid derivatives, the method for preparation thereof and the uses thereof
US20190350951A1 (en) * 2015-09-17 2019-11-21 Entrechem, S.L. Combinations of a mithramycin analogue and another chemotherapeutic agent for the treatment of triple negative breast cancer
US20210155932A1 (en) * 2017-07-21 2021-05-27 Novartis Ag Compositions and methods to treat cancer
US20220296622A1 (en) * 2019-09-16 2022-09-22 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of swi-snf mutant tumors

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