CN-121987635-A - Application of JTC801 as giant bubble cell death inducer in resisting tumor

Abstract

The invention provides an application of JTC801 as a giant bubble cell death inducer in resisting tumor. In particular, JTC801 is used as a small molecule kinase inhibitor drug, has good death induction effect on tumor cells, especially uveal melanoma cells, and the induced cell death mode is not classical apoptosis, pyrodeath, iron death and the like, but is a giant bubble type death mode. This death mode is similar to giant bubble death in that a large amount of vacuoles accumulate in cytoplasm, but unlike giant bubble death mode, this death mode is not limited to the fusion of lysosomes and megapotions and is therefore defined as a giant bubble-like death mode. Therefore, JTC801 has good application prospect in tumor treatment, especially in grape membrane melanoma treatment as a newly discovered giant bubble cell death inducer.

Inventors

• HUANG MINGYAN
• Zhu Ha
• JI XINPEI
• LIU QIUYAN
• YU YIZHI

Assignees

• 中国人民解放军海军军医大学

Dates

Publication Date

20260508

Application Date

20241128

Claims (10)

1. Use of jtc801 as a giant bubble cell death inducer.
2. 2. The use according to claim 1, wherein the cells are uveal melanoma tumor cells.
3. 3. The giant bubble cell death inducer is characterized in that the active component is JTC801 and also comprises pharmaceutically usable auxiliary materials.
4. Use of jtc801 as a giant bubble cell death inducer in the preparation of an antitumor drug.
5. 5. The use according to claim 4, wherein the tumour is uveal melanoma.
6. 6. The use according to claim 5, wherein JTC801 is combined with other anti-uveal melanoma drugs.
7. 7. An anti-tumor giant bubble cell death-inducing pharmaceutical composition comprising: (i) A therapeutically effective amount of JTC801; (ii) Pharmaceutically or immunologically acceptable carriers or excipients.
8. 8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is an oral formulation, an intratumoral injection formulation, or an intraocular injection formulation.
9. 9. The pharmaceutical composition of claim 7, wherein the tumor is uveal melanoma.
10. 10. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is used in combination with other anti-uveal melanoma drugs.

Description

Application of JTC801 as giant bubble cell death inducer in resisting tumor Technical Field The invention belongs to the technical field of biological medicines, and relates to application of cell death induction and related medicines. In particular to an action mechanism and death effect of a small molecule kinase inhibitor JTC801 serving as an inducer of giant bubble cell death, and an implementation method and application thereof in anti-tumor treatment. Background Cell death is a complex and interrelated process that plays a vital role in maintaining tissue homeostasis and preventing disease, and targeting cell death processes can be used to inhibit tumor progression, one of the viable tumor treatment strategies. Most tumor cells present a classical death mode, namely the phenomenon that apoptosis resists in the treatment process, and searching other alternative death modes as tumor treatment targets helps to improve the treatment effective rate of tumor patients. Uveal melanoma (Uveal melanoma, UM) is a type of malignancy in the adult human eye, and is also the most common type of melanoma next to cutaneous melanoma, with characteristics different from cutaneous melanoma. UM has very strong invasiveness and extremely high malignancy, more than 50% of diagnosed patients can have blood metastasis, the liver is involved (more than 90%), half life of liver metastasis patients is only 4-6 months, and 2 years of life is not more than 8%. In addition, compared with foreign patients, UM patients in China have lower onset ages (47.3 v.s.60) and need to be paid attention and paid attention. Although several strategies such as CAR-T, DC vaccine, TCR/anti-CD3 bispecific fusion protein targeting HLA-0201 restricted tumor antigen peptide gp100 (Tebentafusp/IMCgp 100) have achieved a certain success in UM patients in recent years of immune checkpoint therapy typified by PD-1/PD-L1 antibodies, the overall survival of patients has not been significantly improved. Therefore, development of new therapeutic agents is needed to improve the therapeutic effect of UM, prolong the survival time of patients, and improve the survival quality of patients. The human kinase group consists of about 560 protein kinases, which play an important role in inflammation, metabolic diseases and tumorigenesis and development by mediating protein phosphorylation and dephosphorylation to participate in physiological processes such as cell proliferation, apoptosis, subcellular translocation, and the like. In 2001, the FDA approved the first kinase inhibitor (MKI) for Chronic Myelogenous Leukemia (CML) treatment, marking the rise of molecular targeted therapies, also made MKI a popular choice for tumor therapy. Currently, 71 Small Molecule Kinase Inhibitors (SMKI) are approved by the FDA and are mostly used for tumor treatment, for example, kinase inhibitors against EGFR mutations have achieved good therapeutic effects in non-small cell lung cancer, and can significantly improve patient survival. However, novel kinase inhibitors against tumors such as UM are still in the research stage and no clear therapeutic effect has yet emerged. UM is a major feature in that more than about 90% of patients carry activating mutations in the G protein subunits Q and 11 (GNAQ/11) genes, activating the intracellular mitogen-activated protein kinase (MAPK) signaling pathway. One ongoing phase I/II clinical trial (NCT 03947385) data shows that Protein Kinase C (PKC) inhibitor Darovasertib (IDE 196) exhibits good therapeutic efficacy in metastatic UM patients and is approved by the FDA for orphan drug. Therefore SMKI is expected to bring new hope for UM treatment. SMKI capable of inducing UM to generate a novel death mode is mined, and the method has important scientific significance and clinical value for improving the treatment effect of malignant UM tumors. Disclosure of Invention The invention is carried out on the basis of the research, and small molecule kinase inhibitor library is adopted to screen small molecule inhibitors with strong tumor cell killing toxicity on human UM cell lines and explore the mode of inducing tumor cell death. The research of the invention discovers that JTC801 has good death induction activity in a human UM cell line, and the death mode induced by the JTC801 is not classical apoptosis, pyro-death, iron death and the like, but giant bubble death. The death mode is similar to giant bubble death, and a large amount of vacuoles accumulate in cytoplasm, but unlike the classical giant bubble death mode, the death mode does not have the phenomenon that fusion of lysosomes and giant pinocytosis is inhibited, and is accompanied by dysfunctions and metabolic disorders of cell organelles such as lysosomes, mitochondria and the like, so the death mode is defined as a giant bubble death mode. Therefore, JTC801 has good application prospect in tumor treatment, especially in grape membrane melanoma treatment as a newly discovered giant bubble ce