Search

CN-121971440-A - Use of Lycobetaine in preparation of SHMT2 protein targeted inhibitor

CN121971440ACN 121971440 ACN121971440 ACN 121971440ACN-121971440-A

Abstract

The invention discloses an application of Lycobetaine in preparation of a SHMT2 protein targeting inhibitor. The invention adopts a molecular docking technology to obtain 11 candidate compounds, and CCK-8 cell viability experiments show that Lycobetaine has better antiproliferative activity on non-small cell lung cancer A549 and H1299 cells than a standard SHMT2 inhibitor SHIN1.Western blot results showed that Lycobetaine dose-dependently down-regulated SHMT2 expression without affecting SHMT1. The gene knockout experiments indicate that Lycobetaine's antiproliferative activity is dependent on SHMT2 expression. In vitro experiments and organoid models show that Lycobetaine significantly inhibited tumor growth and induced structural collapse and volume reduction of tumor organoids. Lycobetaine can be used as SHMT2 protein targeted inhibitor for tumor treatment.

Inventors

  • ZENG YUANYUAN
  • HUANG JIANAN
  • CHEN YILI
  • WANG ANQI
  • ZHU JIANJIE
  • DU WENWEN
  • LIU ZEYI

Assignees

  • 苏州大学附属第一医院

Dates

Publication Date
20260505
Application Date
20260316

Claims (10)

  1. The application of Lycobetaine in preparation of a SHMT2 protein targeting inhibitor is characterized in that the structural formula of Lycobetaine is shown as the formula (I): (I)。
  2. 2. The use according to claim 1, wherein Lycobetaine is capable of degrading or inhibiting SHMT2, wherein Lycobetaine binds to SHMT2 protein and the binding target is located at Thr411 amino acid position of SHMT2 protein.
  3. The application of Lycobetaine in preparing a medicament for preventing and/or treating SHMT2 mediated related diseases is characterized in that the structural formula of Lycobetaine is shown as the formula (I): (I)。
  4. 4. The use according to claim 3, wherein said SHMT 2-mediated related diseases include neoplasms, autoimmune diseases, respiratory diseases, metabolic and circulatory related diseases and neurodegenerative diseases.
  5. 5. The use according to claim 4 wherein the neoplasm comprises breast cancer, ovarian cancer, gastric cancer, colorectal cancer, lung cancer, pancreatic cancer, liver cancer, glioblastoma, chronic lymphocytic leukemia, acute lymphocytic leukemia and multiple myeloma.
  6. 6. The use according to claim 5, wherein the tumour is lung cancer.
  7. 7. The use according to claim 6, wherein preventing and/or treating a tumor comprises: inhibiting the cell viability of tumor cells; And/or inhibiting proliferation of tumor cells; And/or promoting apoptosis of tumor cells; and/or inducing a breakdown and volume reduction of the tumor organoid structure; And/or inhibiting tumor growth.
  8. 8. Use according to claim 3, wherein Lycobetaine is used alone or in combination with other drugs or in combination with a drug carrier.
  9. 9. The pharmaceutical composition is characterized by comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is Lycobetaine or pharmaceutically acceptable salt thereof, and the structural formula of Lycobetaine is shown as formula (I): (I)。
  10. 10. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable carrier comprises excipients, fillers, binders, wetting agents, disintegrants, diluents and/or surfactants.

Description

Use of Lycobetaine in preparation of SHMT2 protein targeted inhibitor Technical Field The invention belongs to the technical field of biological medicines, and relates to an application of Lycobetaine in preparation of a SHMT2 protein targeting inhibitor. Background SHMT2 (serine hydroxymethyltransferase 2) is a key member of the serine hydroxymethyl transferase family, is used as pyridoxal phosphate dependent enzyme, is mainly located in mitochondria, catalyzes the interconversion of serine and glycine, and simultaneously participates in important biological processes such as single carbon unit metabolism, nucleotide synthesis, redox balance regulation and the like, so as to provide necessary raw materials and energy for cell growth and division. In recent years, research shows that the abnormally high expression of SHMT2 is closely related to the occurrence and development of various tumors, such as solid tumors (such as lung cancer, colon cancer, pancreatic cancer, breast cancer, bladder cancer and the like) and malignant tumors of a blood system (such as T cell acute lymphoblastic leukemia and the like). In solid tumors, SHMT2 promotes tumor progression through multiple mechanisms. In lung cancer, high SHMT2 expression is related to the malignancy degree of the tumor, the proliferation capacity of tumor cells can be enhanced by regulating m6A modification, promoting cell cycle progress and maintaining redox balance, in colon cancer, the increase of SHMT2 expression is closely related to poor prognosis of a patient, cell homeostasis is maintained by regulating autophagy adapter protein SQSTM1 expression, the proliferation of tumor cells is promoted, in pancreatic cancer, the increase of SHMT2 expression is related to poor survival of the patient, one-carbon metabolism of mitochondria involved in the SHMT2 is used for providing growth advantages for the tumor cells, the targeted SHMT2 can damage redox balance of the tumor cells, in breast cancer, the expression level of the SHMT2 is positively related to tumor grading and can be used as an independent prognostic factor, the invasion and migration capacity of the tumor cells are enhanced by up-regulating HAX1 expression, and in bladder cancer, the high SHMT2 expression is used for promoting tumor cell proliferation by maintaining redox balance and is related to poor prognosis of the patient. In hematological malignancies, SHMT2 expression is significantly elevated in human T-ALL cell lines, providing necessary metabolic support for tumor cell proliferation by participating in serine-glycine-one carbon metabolic pathways, promoting malignant proliferation. Therefore, the development of high-efficiency, specific SHMT2 inhibitors is an important research direction for the treatment of the above-mentioned SHMT 2-related tumors. Currently, various SHMT2 inhibitors (such as SHIN1, SHIN2, AGF347, etc.) have entered the preclinical research stage and exhibit good antitumor activity in various tumor models, but the existing SHMT2 inhibitors still have some drawbacks, such as poor pharmacokinetic parameters, insufficient targeting specificity, susceptibility to induce cell compensation reactions (such as SHMT 1-mediated functional compensation), strong cytotoxicity of part of the inhibitors, etc., which limit their advancement to clinical trials. In addition, SHMT2 is closely related to normal tissue metabolism, and how to improve the selectivity of inhibitors to tumor cells and reduce the damage to normal cells is also a problem to be solved. Up to now, lycobetaine has not been reported to have a SHMT2 inhibitory activity and to be useful for the preparation of SHMT2 inhibitors or for the treatment of SHMT2 mediated related diseases. Disclosure of Invention Aiming at the defects of the prior art, the invention provides Lycobetaine application in preparation of a SHMT2 protein targeting inhibitor, small molecules combined with the SHMT2 protein are screened through virtual screening and functions, wherein Lycobetaine shows the targeting capability of the SHMT2 protein, experimental verification shows that Lycobetaine inhibits cancer cell proliferation and tumor growth in vitro and in vivo of lung cancer, and the SHMT2 protein degradation is induced, so that the anti-tumor effect is realized, which shows that Lycobetaine can be used as a SHMT2 protein targeting inhibitor and is a novel lead compound for treating tumors. The technical scheme provided by the invention is as follows: The invention provides an application of Lycobetaine in preparation of a SHMT2 protein targeting inhibitor, wherein the structural formula of Lycobetaine is shown as a formula (I): (I)。 further, lycobetaine is capable of degrading or inhibiting SHMT2, lycobetaine binds to SHMT2 protein and the binding target is located at the Thr411 amino acid position of SHMT2 protein. The invention also provides an application of Lycobetaine in preparing a medicament for preventing and/or treating SHMT2 m