CN-122005574-A - Application of monocarboxylic acid transporter 1 inhibitor in preparation of medicines for preventing, relieving and/or treating pancreatic cancer

Abstract

The application relates to application of a monocarboxylic acid transporter 1 inhibitor in preparation of a medicament for preventing, relieving and/or treating pancreatic cancer. The use of MCT1 inhibitors effectively reduced lactate levels in pancreatic astrocytes PSCs, thereby inhibiting lactogenesis of Vps34 and blocking the process of activation of autophagy-dependent PSCs mediated by lactate. MCT1 inhibitors further reduced secretion of the downstream chemokines CXCL9 and CXCL10 by inhibiting PSCs activation. Because CXCL9 and CXCL10 are key factors for inducing cd8+ T cells to up-regulate PD-1 expression through CXCR3 and STAT3 signaling pathways, MCT1 inhibitors essentially cut off the induction signal that leads to depletion of cd8+ T cells upstream, thereby being capable of inhibiting the in vivo growth and in situ tumorigenicity capacity of pancreatic cancer, and achieving the goal of preventing, alleviating and/or treating pancreatic cancer.

Inventors

• ZHUO WENFENG
• ZHAO GANG
• ZENG ZHU
• HU YUHANG
• HU PING
• HAN SHENGBO

Assignees

• 华中科技大学同济医学院附属协和医院

Dates

Publication Date

20260512

Application Date

20260316

Claims (8)

1. 1. Use of a monocarboxylic acid transporter 1 inhibitor for the manufacture of a medicament for the prevention, alleviation and/or treatment of pancreatic cancer, said monocarboxylic acid transporter 1 inhibitor reducing lactate levels in pancreatic stellate cells, inhibiting lactate formation of autophagy-critical regulatory protein Vps 34.
2. 2. Use of the monocarboxylic acid transporter 1 inhibitor according to claim 1 for the preparation of a medicament for the prevention, alleviation and/or treatment of pancreatic cancer, characterized in that: The monocarboxylic acid transporter 1 inhibitor is a compound shown in a formula (I) or pharmaceutically acceptable salt thereof.
3. 3. A medicament for preventing, alleviating and/or treating pancreatic cancer is characterized in that the medicament comprises an active substance, wherein the active substance comprises a monocarboxylic acid transporter 1 inhibitor, and the monocarboxylic acid transporter 1 inhibitor reduces the lactic acid level in pancreatic stellate cells and inhibits the lactate formation of autophagy key regulatory protein Vps 34.
4. 4. A medicament for the prevention, alleviation and/or treatment of pancreatic cancer according to claim 3, characterized in that: The monocarboxylic acid transporter 1 inhibitor is a compound shown in a formula (I) or pharmaceutically acceptable salt thereof.
5. 5. The pharmaceutical composition for preventing, alleviating and/or treating pancreatic cancer of claim 3, further comprising a pharmaceutically acceptable carrier.
6. 6. A pharmaceutical composition for preventing, alleviating and/or treating pancreatic cancer according to claim 5, wherein said pharmaceutically acceptable carrier is selected from the group consisting of pharmaceutically acceptable solid and liquid excipients.
7. 7. The pharmaceutical agent for preventing, alleviating and/or treating pancreatic cancer according to claim 5, wherein said agent further comprises a buffer solution selected from the group consisting of acetate, citrate, borate and phosphate.
8. 8. A pharmaceutical composition for preventing, alleviating and/or treating pancreatic cancer according to claim 3, wherein said pharmaceutical composition is formulated as a tablet, capsule, powder, suppository, injection or nasal spray.

Description

Application of monocarboxylic acid transporter 1 inhibitor in preparation of medicines for preventing, relieving and/or treating pancreatic cancer Technical Field The application relates to the technical field of biological medicines, in particular to application of a monocarboxylic acid transport protein 1 inhibitor in preparation of a medicine for preventing, relieving and/or treating pancreatic cancer. Background Pancreatic cancer (PANCREATIC CANCER, PC) is a tumor of extremely high malignancy of the digestive system, and is called "King in cancer". Although current cancer immunotherapy shows significant efficacy in various solid tumors, pancreatic cancer responds poorly to existing Immune Checkpoint Blocking (ICB) therapies, including PD-1 (Programmed cell death protein-1,programmed death-1)/PD-L1 (Programmed CELL DEATH LIGAND, programmed death ligand-1) inhibitors and CTLA-4 (cytotoxic T lymphocyte-associated antigen 4,cytotoxic T lymphocyte-associated antigen-4) inhibitors, due to its highly immunosuppressive tumor microenvironment (Tumor microenvironment, TME), with limited therapeutic efficacy. Pancreatic stellate cells (PANCREATIC STELLATE CELLS, PSCs) serve as the primary source of pancreatic cancer-associated fibroblasts (CAF) and play a key role in maintaining the normal physiological structure of the pancreas. However, activated pancreatic astrocytes PSCs mediate the formation of a pancreatic cancer immunosuppressive microenvironment by matrix reprogramming, recruitment of myelogenous suppressor cells (MDSCs), and induction of macrophage M2 polarization. Therefore, searching for a new target and related strategies capable of regulating and controlling activation of pancreatic astrocytes PSCs has important clinical significance for improving the effect of pancreatic cancer immunotherapy. Disclosure of Invention The application provides an application of a monocarboxylic acid transport protein 1 inhibitor in preparing a medicament for preventing, relieving and/or treating pancreatic cancer, which can inhibit the activity of pancreatic astrocytes PSCs, further can inhibit the in-vivo growth and in-situ tumorigenicity of pancreatic cancer, and achieves the purposes of preventing, relieving and/or treating pancreatic cancer. In a first aspect, embodiments of the present application provide the use of a monocarboxylic acid transporter 1 inhibitor for the manufacture of a medicament for the prevention, alleviation and/or treatment of pancreatic cancer. With reference to the first aspect, in one embodiment, the monocarboxylic acid transporter 1 inhibitor is a compound of formula (I): 。 With reference to the first aspect, in one embodiment, the monocarboxylic acid transporter 1 inhibitor reduces lactate levels in pancreatic stellate cells, inhibiting lactate formation by autophagy-critical regulatory protein Vps 34. In a second aspect, embodiments of the present application provide a medicament for preventing, alleviating and/or treating pancreatic cancer, the medicament comprising an active substance comprising a monocarboxylic acid transporter 1 inhibitor. With reference to the second aspect, in one embodiment, the monocarboxylic acid transporter 1 inhibitor is a compound of formula (I): 。 with reference to the second aspect, in one embodiment, the monocarboxylic acid transporter 1 inhibitor reduces lactate levels in pancreatic stellate cells, inhibiting lactate formation by autophagy-critical regulatory protein Vps 34. With reference to the second aspect, in one embodiment, the medicament further comprises a pharmaceutically acceptable carrier. With reference to the second aspect, in one embodiment, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable solid or liquid excipients. With reference to the second aspect, in one embodiment, the medicament further comprises a buffer solution selected from the group consisting of acetate, citrate, borate, or phosphate. With reference to the second aspect, in one embodiment, the drug is administered in the form of a tablet, capsule, powder, suppository, injection or nasal spray. The technical scheme provided by the application has the beneficial effects that: There is a large amount of lactic acid produced by glycolysis of tumor cells in the pancreatic cancer tumor microenvironment TME. MCT1 inhibitors specifically block the MCT1 transporter protein on the membrane surface of pancreatic astrocytes PSCs, thereby cutting off the passage of lactic acid into pancreatic astrocytes PSCs. Applicants' studies have found that lactic acid entry into pancreatic astrocytes PSCs results in lysine lactate modification of autophagy-critical regulatory protein Vps34 (specific sites are K356 and K781). The use of MCT1 inhibitors effectively reduced lactate levels in pancreatic astrocytes PSCs, thereby inhibiting lactogenesis of Vps34 and blocking the process of activation of autophagy-dependent PSCs mediated by lactate. Activated pancreatic astr