EP-4739319-A1 - COMPOSITIONS COMPRISING AN INHIBITOR OF GALECTIN-3

EP4739319A1EP 4739319 A1EP4739319 A1EP 4739319A1EP-4739319-A1

Abstract

The present disclosure provides a composition comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and/or a compound of Formula II, or pharmaceutically acceptable salt thereof, for use in inhibiting Galectin-3. The composition may be for use in the treatment and/or prevention of a disease, disorder, state or condition wherein inhibiting Galectin-3 would be beneficial for the treatment and/or prevention of the disease, disorder, state or condition. The disease, disorder, state or condition may be cancer, cancer metastasis, fibrosis, inflammation, diabetes and/or one or more other disease, disorder, state or condition affected and/or mediated by Galectin-3.

Inventors

YU, Lu-Gang

Assignees

University of Liverpool

Dates

Publication Date: 20260513
Application Date: 20240703

Claims (20)

1. A composition comprising: a compound of Formula I, or a pharmaceutically acceptable salt thereof, and/or a compound of Formula II, or a pharmaceutically acceptable salt thereof, for use in inhibiting Galectin-3.
2. The composition of claim 1, wherein the composition is for use in the treatment and/or prevention of a disease, disorder, state or condition wherein inhibiting Galectin-3 would be beneficial for the treatment and/or prevention of the disease, disorder, state or condition. 3. The composition of claim 2, wherein the disease, disorder, state or condition is cancer, cancer metastasis, fibrosis, inflammation, diabetes and/or one or more other disease, disorder, state or condition affected and/or mediated by Galectin-
3.
4. A composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, and/or a compound of Formula II, or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a disease, disorder, state or condition, wherein the disease, disorder, state or condition is cancer, cancer metastasis, fibrosis, diabetes, inflammation and/or one or more other disease, disorder, state or condition affected and/or mediated by Galectin- 3.
5. The composition of any one of claims 2 to 4, wherein the disease, disorder, state or condition is cancer and wherein the treatment and/or prevention of cancer comprises inhibiting or preventing metastasis, cancer reappearance after initial therapeutic treatment or intervention, cancer cell proliferation, tumour growth, angiogenesis, or immunosuppression.
6. The composition of any one of claims 2 to 4, wherein the disease, disorder, state or condition is cancer metastasis and wherein the treatment and/or prevention of cancer metastasis comprises inhibition of the motility of cancer or tumour cells, inhibition of angiogenesis, inhibition of immunosuppression, inhibition of the dissemination and invasiveness of cancer cells leading to inhibition of metastatic tumour growth, inhibitor of the dissemination and invasiveness of cancer cells leading to improved clinical outcome for the subject.
7. The composition of any one of claims 2 to 6, wherein the cancer is one or more of: breast cancer, pancreatic cancer, lung cancer, melanoma, colorectal cancer, head and neck cancer, ovarian cancer, oesophageal cancer thyroid cancer, bladder cancer, urinary system cancer, prostate cancer, digestive or gastrointestinal tract cancer, leukaemia, lymphoma, liver cancer or musculoskeletal cancer.
8. The composition of any one of claims 2 to 4, wherein the disease, disorder, state or condition is fibrosis and wherein the treatment and/or prevention of fibrosis comprises treatment/prevention of a fibrotic disorder, a fibrotic condition, a fibroprol iterative disease, or a disorder or state of wound-healing response that is out of control.
9. The composition of claim 8, wherein the fibrotic disorder, fibrotic condition, fibroprol iterative disease, or a disorder or state of wound-healing response that is out of control is one or more of: scarring or wound healing abnormalities, chronic or acute inflammation, chronic graft rejection, or a fibrotic condition or fibrosis affecting the heart, brain, lungs, liver, kidneys, heart or vascular system, mediastinum, bone, retroperitoneum, skin, digestive or gastrointestinal tract, connective tissue, eye or muscles.
10. The composition of any one of claims 2 to 4, wherein the disease, disorder, state or condition is inflammation and wherein the treatment and/or prevention of inflammation comprises treatment/prevention of an inflammation-related disease or a condition caused by inflammation.
11. The composition of claim 10, wherein the inflammation-related disease or a condition caused by inflammation is one or more of: acute or chronic organ transplant rejection, graft- versus- host disease, inflammatory bowel disease, inflammatory skin disease, multiple sclerosis, arteriosclerosis, pancreatitis, acute bronchitis, chronic bronchitis, Alzheimer's disease, inflammatory lung disease, inflammatory skin disease, Acute bronchiolitis, folliculitis, chronic bronchiolitis, musculoskeletal pain or connective tissue inflammation, osteoarthritis, gout, spondyloarthropathy, Reiter's syndrome, psoriatic arthropathy, inflammation caused by bacterial, fungal, and viral infections one or more diseases, atherosclerosis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, nephritis, Parkinson's disease, chronic inflammation, one or more neurodegenerative diseases or disorders caused by tumours caused by chronic inflammation and aging caused by chronic inflammation, inflammatory symptoms caused by autoimmune diseases including ulcerative colitis (UC) and Crohn's disease (CD), lupus erythematosus, hyperthyroidism, IgA nephritis, type I or type II diabetes and its complications, dry eye syndrome, rheumatoid arthritis, simple obesity, ankylosing spine inflammation, bronchial asthma, neurodermatitis, ulcerative colitis, oral ulcers, psoriasis, vitiligo, Behget's disease, autoimmune iridocyclitis, autoimmune eczema, autoimmune uveitis, One or more of autoimmune conjunctivitis, autoimmune dry eye, autoimmune glaucoma, autoimmune cataract, allergic rhinitis, irritable bowel syndrome, pruritus.
12. The composition of any one of claims 2 to 4, wherein the disease, disorder, state or condition is diabetes and wherein the treatment and/or prevention of fibrosis comprises treatment/prevention of type I or type II diabetes and/or any related diabetic-associated disease or condition such as obesity.
13. The composition of any one of claims 2 to 4, wherein the disease, disorder, state or condition is one or more other disease, disorder, state or condition affected and/or mediated by Galectin-3, preferably wherein the one or more other disease, disorder, state or condition which is affected and/or mediated by Galectin-3 is Asthma, Atherosclerosis, Atopic Dermatitis, Cerebral infarction, COPD, Degenerative Aortic Stenosis, Endometriosis, Encephalitis, Gastritis, HIV infection, Interstitial lung disease, Juvenile Idiopathic Arthritis, CVD mortality, Non-alcoholic steatohepatitis (NASH), Obesity, Pneumonia, Pulmonary hypertension, Plaque Psoriasis, Q Fever, Rheumatoid Arthritis, Systemic Sclerosis, Urinary tract infections, Covid-19, sepsis, Thrombosis, Venous Thrombosis, Wound Healing, Cardiac syndrome X (CSX), Yeast infection-Candidiasis or Zoster- related pain (allodynia).
14. The composition of any preceding claim, wherein the composition further comprises one or more pharmaceutically or cosmetically acceptable ingredients or excipients, preferably one or more of the following: pharmaceutically acceptable carriers, adjuvants, , excipients, diluents, fillers, buffers, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants, wetting agents, masking agents, colouring agents, fragrance agents and penetration agents, preferably wherein the composition is in a form suitable for oral use.
15. The composition of any preceding claim, wherein the compound of Formula I and/or the compound of Formula II is in a metabolized and/or hydrolysed and/or oxidised form, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
16. The composition of any preceding claim, wherein the composition further comprises one or more other active agent, preferably one or more additional antitumour agents, and/or chemotherapy agents, and/or anti-metastatic agents, and/or radiotherapy agents and/or immunotherapeutic agents and/or anti- fibrosis/fibrotic agents and/or anti-inflammation/inflammatory agents and/or one or more other Galectin inhibitor.
17. An in vitro or in vivo method of inhibiting Galectin-3, the method comprising administering an effective amount of the composition of any one of claims 1 to 16.
18. A method of treating and/or preventing a disease, disorder, state or condition, wherein inhibiting Galectin-3 would be beneficial for the treatment of the disease, disorder state or condition, the method comprising administering to the subject an effective amount of the composition of any one of claims 1 to 16.
19. The method of claim 17, wherein the disease, disorder, state or condition is cancer, cancer metastasis, fibrosis, inflammation, diabetes and/or one or more other disease, disorder, state or condition affected and/or mediated by Galectin- 3.
20. A method of treating and/or preventing a disease, disorder state or condition, wherein the disease, disorder, state or condition is cancer, cancer metastasis, fibrosis, inflammation, diabetes, and/or one or more other disease, disorder, state or condition affected and/or mediated by Galectin-3, the method comprising administering to the subject an effective amount of the composition of any one of claims 1 to 16.

Description

COMPOSITIONS COMPRISING AN INHIBITOR OF GALECTIN-3 The present disclosure relates to the prevention and/or treatment of cancer and/or cancer metastasis and/or fibrosis and/or inflammation and/or diabetes and/or other conditions which are affected and/or mediated by Galectin-3. More specifically, the present disclosure relates to the prevention and/or treatment of cancer and/or cancer metastasis and/or fibrosis and/or inflammation and/or diabetes by inhibiting the activity of Galectin-3. The present disclosure relates to compounds and compositions for inhibiting the activity of Galectin-3. The present disclosure relates to methods and kits for inhibiting the activity of Galectin-3, particularly in methods of treatment for cancer and/or cancer metastasis and/or fibrosis and/or inflammation and/or diabetes and/or one or more other diseases, disorders, states or conditions which are affected and/or mediated by Galectin-3. BACKGROUND In the UK cancer is a leading cause of death, accounting for one out of every four deaths with a total of more than 150,000 deaths each year. Nearly half of all people will develop cancer during their lifetime with more than 500,000 new cancer cases diagnosed each year. Despite enormous effort, effective treatment of this disease still remains a big challenge. It is increasingly believed that therapies targeted at specific molecules or mechanisms, especially multi-modal treatments hold the solution for more effective cancer treatments. Cancer refers to a group of diseases which are characterised by abnormal and/or uncontrolled cell growth. These cells can form tumours, a tumour can develop when cells reproduce too quickly. The United States National Cancer Institute defines a tumour as "an abnormal mass of tissue that results when cells divide more than they should or do not die when they should." Tumours can be any size, and can roughly be characterised as benign, premalignant or malignant. Malignant tumours can grow and spread to other parts of the body, for example via the blood or lymphatic systems. Benign tumours do not invade or destroy nearby tissues, or spread to other areas of the body. Premalignant tumours have not yet begun to spread, but may soon. Galectin-3 (GAL3) is a family member of the galactoside-binding proteins and is expressed by many types of human cells, in particular epithelial and immune cells. It is commonly overexpressed by most types of solid tumours such as breast, lung, colon, pancreatic, prostate, digestive or gastrointestinal tract, urinary system, thyroid and melanoma [Newlaczyl, A.U. and L.G. Yu, Galectin-3: A-jack-of-all- trades in cancer. Cancer Lett, 2011. 313: p. 123-128, Liu, F.-T.T. and G.A. Rabinovich, Gaiectins as modulators of tumour progression. Nature Reviews Cancer, 2005. 5(1): p. 29-41]. Extensive research over the past decades has revealed that Galectin-3 is a very important promoter of cancer progression and metastasis. It does so through multiple mechanisms intracellularly and extracellularly. Extracellular Galectin-3 interacts with galactoside-terminated glycans expressed on a number of cell surface molecules such as mucin proteins, growth factors and cell adhesion molecules (e.g. MUC1, MUC16, epidermal growth factor (EGF), transforming growth factor p (TGFp) receptors, integrins) and basement matrix proteins that promote tumour cell adhesion, invasion and angiogenesis in cancer progression and metastasis. Extracellular Galectin-3 induces T cell apoptosis, prevents T-cell infiltration in the tumour microenvironment and dampens anti-tumour immunity in the body [Gordon- Alonso, M., et al., Gaiectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun, 2017. 8(1): p. 793]. Galectin-3 is also known to promote tumour cell proliferation, establishment of metastatic niches, oncogenic signalling, apoptosis resistance and cell cycle progression when present intracellularly. Levels of circulating Galectin-3 are markedly elevated in cancer patients, in particular those with metastasis [Barrow, H., et al., Serum Gaiectin-2,-4, and -8 Are Greatly Increased in Coion and Breast Cancer Patients and Promote Cancer Cell Adhesion to Blood Vascular Endothelium. Clinical Cancer Research, 2011. 17(22): p. 7035- 7046]. Circulating Galectin-3 has been found to have an important role in promoting circulating tumour cell metastatic spread to remote organs by interaction with disseminating tumour cells [Zhao, Q., et al., Interaction between circulating gaiectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer, 2010. 9: p. 154, Zhao, Q., et al., Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res, 2009. 69(17): p. 6799-806], as well as with the vascular endothelium [Chen, C., et al., Increased circulation of gaiectin-3 in cancer induces secretion of metastasis-promoting cy