CN-122010796-A - Small molecule inhibitor based on lactate dehydrogenase targeting design and application thereof

Abstract

The invention discloses a small molecule inhibitor based on lactate dehydrogenase targeting design and application thereof, belonging to the field of biological medicine, wherein the small molecule inhibitor is a benzenesulfonamide compound or pharmaceutically acceptable salt thereof, the structure of the small molecule inhibitor is shown as follows, and the small molecule inhibitor can be used as a lactate dehydrogenase inhibitor and is suitable for treating and/or preventing diseases mediated by lactate dehydrogenase.

Inventors

• ZHAO BO
• Jie Jiawei
• CHEN XUEYING
• LV LING
• WANG HAO
• Liu jiangxi
• ZHANG DONG
• CHEN LIUYANG

Assignees

• 南京师范大学
• 徐州医科大学

Dates

Publication Date

20260512

Application Date

20260410

Claims (9)

1. 1. The small molecule inhibitor is a benzenesulfonamide compound or pharmaceutically acceptable salt thereof, and the structure of the small molecule inhibitor is shown as the following formula I: ; Wherein R 1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxy, carboxy, amino, halogen, cyano, nitro, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, said heterocycle being a heterocycloalkyl ring or a heterocycloalkenyl ring, one or more hydrogen atoms on said substituent being substituted with one or more substituents selected from halogen, alkoxy of 1-3 carbons, trifluoromethyl, trifluoromethoxy, methylthio or trifluoromethylthio.
2. 2. The lactate dehydrogenase-targeted design-based small molecule inhibitor of claim 1, wherein the small molecule inhibitor is selected from any one of the following: 。
3. 3. use of a small molecule inhibitor based on a lactate dehydrogenase targeting design according to claim 1 or 2 for the preparation of a lactate dehydrogenase inhibitor.
4. 4. The use according to claim 3, wherein the small molecule inhibitor inhibits the production of lactic acid by binding to lactate dehydrogenase.
5. 5. Use of a small molecule inhibitor based on a lactate dehydrogenase targeting design according to claim 1 or 2 for the manufacture of a medicament for the treatment and/or prevention of lactate dehydrogenase mediated diseases.
6. 6. The use according to claim 5, wherein the lactate dehydrogenase mediated disease comprises a disease of tumor cell metabolism and a disease of liver cell metabolism.
7. 7. The use according to claim 6, wherein the disease comprises liver cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer and skin cancer.
8. 8. A pharmaceutical composition for the treatment and/or prevention of lactate dehydrogenase-mediated diseases, comprising the small molecule inhibitor according to claim 1 or 2 as an active ingredient and a pharmaceutically acceptable adjuvant.
9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.

Description

Small molecule inhibitor based on lactate dehydrogenase targeting design and application thereof Technical Field The invention belongs to the field of biological medicine, and particularly relates to a small molecule inhibitor based on lactate dehydrogenase targeting design. Background Hepatocellular carcinoma (hepatocellular carcinoma, HCC) is one of the most common neoplastic diseases worldwide, which involves multiple etiologies, but liver inflammation caused by different etiologies all have the same pathological process, i.e. inflammatory cancerous transformation of the liver. In a chronic inflammatory state, the inflammatory microenvironment promotes abnormal activation of glycolytic pathways through remodelling of cell energy metabolism, so that lactic acid is accumulated in a large amount, and normal liver cells are driven to transform to a malignant phenotype through mechanisms such as histone lactate modification and the like. Lactate Dehydrogenase (LDH) is used as a key enzyme in the final link of glycolysis, and subtype A (LDHA) of the lactate dehydrogenase is remarkably expressed in liver cancer tissues and is closely related to tumor proliferation, invasion and metastasis and poor prognosis of patients. The catalytic redox reaction of LDHA is a well-coordinated process, the enzyme acting as a tetramer, each subunit binding the coenzyme NADH. NADH binding induces conformational changes in the enzyme, creating a specific pocket for the substrate pyruvate, which mechanism is transferred from the C4 of NADH nicotinamide loop to the carbonyl carbon of pyruvate via the hydride. This transfer is facilitated by the active site residues in the stable transition state, with the result that pyruvate is reduced to lactate and NADH is oxidized to NAD +. This reaction is critical because the regeneration of NAD + is critical to the duration of glycolysis under conditions of high glycolysis or impaired mitochondrial function. If LDHA is inactive, glycolysis will cease due to depletion of NAD +, resulting in the desired energy failure in the body. Thus, when oxidative phosphorylation is limited, the primary physiological role of LDHA is to maintain glycolytic ATP production. In the case of hepatocellular carcinoma, this basic metabolic pathway becomes the primary driver of the disease. Inflammatory environments induce hypoxia and redox states in the liver, promoting transcriptional upregulation of LDHA through hypoxia-inducible factors (HIFs) and other stress pathways. Overexpression of LDHA leads to metabolic recombination processes, often described as the "Warburg effect", which can lead to excessive lactate production. Accumulation of lactic acid has many deleterious consequences, such as it promotes intracellular acidification, thereby promoting apoptosis and creating an environment conducive to inflammation and fibrosis. Second, high lactate level expression has been demonstrated to directly activate hepatic stellate cells, primary fibrotic cells in the liver, thereby accelerating the development of liver fibrosis, a key step in the progression of cirrhosis. Thus targeted inhibition of LDHA is an attractive target, and blocking lactic acid accumulation has become an important strategy to prevent liver inflammatory cancer transformation. There is currently no FDA approved positive drug for LDHA inhibitors on the market. The reported LDHA inhibitors generally have non-specific effects and poor cell penetrability, such as oxamate (Oxamate), off-target effects, such as phenol (Gossypol) and its derivative FX11, and liver clearance is too high. Disclosure of Invention The invention aims to solve the problems in the prior art and provide a small molecule inhibitor based on a lactate dehydrogenase targeting design, which is suitable for treating and/or preventing a disorder or a disease mediated by lactate dehydrogenase. The present invention provides small molecule compounds having lactate dehydrogenase inhibiting activity as small molecule inhibitors of targeted protein receptors for the treatment of, for example, hepatocellular carcinoma, breast cancer, colon cancer, lung cancer, pancreatic cancer, and skin cancer. It is another object of the present invention to provide a medical use of the small molecule inhibitor. In order to achieve the above purpose, the small molecule inhibitor based on lactate dehydrogenase targeting design is a benzenesulfonamide compound or pharmaceutically acceptable salt thereof, and has a structure shown in the following formula I: Wherein R 1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxy, carboxy, amino, halogen, cyano, nitro, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring