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CN-121991079-A - PROTAC molecules targeting thymidylate synthase and uses thereof

CN121991079ACN 121991079 ACN121991079 ACN 121991079ACN-121991079-A

Abstract

The invention provides preparation and application of PROTAC molecules of targeted degradation thymidylate synthase, and relates to the field of medicines. The invention is based on pyrrolo [2,3-d ] pyrimidine multi-target folic acid antagonists, utilizes connecting chains of different lengths and types to connect with E3 ligase Cereblon (CRBN) ligand, prepares PROTAC molecules of novel folic acid and uses in folic acid related diseases such as cancers. Has a structure shown in the following general formula I:

Inventors

  • XING RUIJUAN
  • HUANG HAILIAN
  • LI YINGAO
  • Su Tongdan
  • WANG LEI

Assignees

  • 河北医科大学

Dates

Publication Date
20260508
Application Date
20260210

Claims (12)

  1. 1. A TS-targeting PROTAC chimera, or a pharmaceutically or physiologically acceptable salt thereof, having the structure of formula I: ; Wherein E3 ligand is a protein ligand in ubiquitin ligase complex, cereblon (CRBN) ligand, linker is a connecting group between target protein ligand and E3 ligase ligand, X is one of-CONH-, -CH 2 SCH 2 -, and R is one of H, methyl, ethyl, isopropyl and tert-butyl.
  2. 2. The chimera according to claim 1, characterized in that the CRBN ligand is selected from thalidomide or its derivatives.
  3. 3. The chimera according to claim 1, wherein the CRBN ligand has the preferred structure shown below: 。
  4. 4. The chimera according to claim 1, characterized in that Linker is-alkylene or-alkoxy or-piperazinyl or-piperidinyl or-1, 2, 3-triazolyl, said-alkylene or-alkoxy or-piperazinyl or-piperidinyl or-1, 2, 3-triazolyl being selected from any one or a combination of more than any of the following groups, wherein n represents a natural number from 1 to 15; 。
  5. 5. the TS-targeted PROTAC chimera or a pharmaceutically or physiologically acceptable salt thereof according to claim 1, wherein the TS-targeted PROTAC chimera is preferably any one of the following compounds Gly-C1 to Gly-C46: ; ; ; ; ; ; ; 。
  6. 6. The method for preparing the PROTAC chimera of targeted degradation TS or pharmaceutically or physiologically acceptable salt thereof according to claim 5, wherein the preparation method adopts different synthetic routes respectively, and the specific synthetic routes are as follows: synthetic route 1: ; synthetic route 2: ; synthetic route 3: ; Synthetic route 4: ; Synthetic route 5: ; synthetic route 6: 。
  7. 7. A pharmaceutical composition comprising the TS-targeting PROTAC chimeric or a pharmaceutically or physiologically acceptable salt thereof of any one of claims 1-5, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
  8. 8. Use of a TS-targeting PROTAC chimera according to any one of claims 1-5, or a pharmaceutically or physiologically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the preparation of a medicament for degrading TS.
  9. 9. Use of a TS-targeting PROTAC chimera according to any one of claims 1-5, or a pharmaceutically or physiologically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the treatment of a folate-associated disease.
  10. 10. Use according to claim 9, characterized in that the folate-associated disease is a tumor.
  11. 11. Use of the TS-targeting PROTAC chimera of any one of claims 1-5 or a pharmaceutically or physiologically acceptable salt thereof or the pharmaceutical composition of claim 7 for anti-tumor, said tumor being gastric cancer, breast cancer, lung cancer, gastric cancer, colon adenocarcinoma, pancreatic cancer, bladder cancer, hepatocellular carcinoma, and cervical cancer.
  12. 12. Use according to claim 11, characterized by a tumor with high FR expression.

Description

PROTAC molecules targeting thymidylate synthase and uses thereof Technical Field The invention relates to the field of medicines, in particular to preparation and application of PROTAC molecules of targeted thymidylate synthase. Background Tumors are still refractory diseases that are severely threatening human health. Tumor cells have the characteristic of unlimited proliferation, and a large amount of DNA is needed as a synthesis raw material in the process, so that the growth process of the tumor cells can be effectively blocked by inhibiting key enzymes in a DNA synthesis path. Folic acid antagonists are an important class of drugs in clinical treatment of tumors, whose core role is to specifically inhibit related enzymes required for DNA synthesis, such as Methotrexate (MTX) which can target the inhibition of dihydrofolate reductase (Dihydrofolate reductase, DHFR) and pemetrexed (Pemetrexed, PMX) which can specifically inhibit thymidylate synthase (THYMIDYLATE SYNTHASE, TS). However, the medicine generally faces the problem of drug resistance in clinical application, and the problem obviously restricts the treatment effect and the clinical application range. The technology of the proteolytic targeting chimera (Proteolysis TARGETING CHIMERAS, PROTAC) has become a research hot spot and an important technical direction in the field of cancer treatment by virtue of a unique action mechanism, and provides a new path for solving the limitation of the traditional medicines. The technical concept is originally proposed by the university of Yersinia Crews professor and the team thereof in 2001, and the core is to exert a therapeutic effect by downregulating the level of target protein by means of the inherent ubiquitin-proteasome degradation pathway of the organism, which is different from the action mode of the traditional medicine which only inhibits the function of the protein, and has irreplaceable advantages. PROTAC the molecule consists of three core domains, a "warhead" structure that specifically binds to the target protein, a ligand that binds to the E3 ubiquitin ligase, and a linker that connects the two domains. The specific action mechanism is that one end of PROTAC molecules is combined with E3 ubiquitin ligase, the other end is combined with target protein, the spatial distance between the two is shortened by a connector, and then E3 ubiquitin ligase is induced to be target protein to modify ubiquitin tag, the ubiquitin-tagged target protein can be recognized and degraded by a proteasome, and PROTAC molecules can be recycled and participate in the next ubiquitination and target protein degradation process. In view of the above advantages, PROTAC technology has demonstrated great potential for overcoming tumor resistance and improving targeted therapeutic specificity, has attracted active layout-related research by large pharmaceutical enterprises worldwide, and has pushed multiple PROTAC molecules into clinical research phase. According to PROTAC on-line database (PROTAC DB) statistics, the number of PROTAC molecules developed at present reaches 6111, and 442 target points can be acted, wherein the target points comprise Androgen Receptor (AR), estrogen Receptor (ER), bruton Tyrosine Kinase (BTK), anaplastic Lymphoma Kinase (ALK), fusion protein BCR-ABL, bromodomain protein 4 (BRD 4), mitogen activated protein kinase 1 (MEK 1), cyclin dependent kinase 4 (CDK 4), epidermal Growth Factor Receptor (EGFR) and the like. However, it is notable that PROTAC molecules related to the target of action of folic acid antagonists are extremely scarce, and there are only 1 reports on the current situation, namely, PROTAC molecules are constructed based on methotrexate and used as DHFR-specific chemical probes in the study published by 2024, RAI GANESHA and the like, while PROTAC molecules of TS have no report on the current situation, and obvious study blank exists in the field. The pyrrolo [2,3-d ] pyrimidine multi-target folic acid antagonist has excellent tumor targeting by virtue of the unique structural advantage, and can become an ideal foundation for constructing TS targeting PROTAC molecules. The compound can be specifically transported into tumor cells through a Folate Receptor (FR) and a Proton-coupled Folate transporter (Proton-coupled Folate transporters, PCFT) which are highly expressed by the tumor cells, and rarely enter normal cells, so that the toxic and side effects on normal tissues are obviously reduced. In addition, after the compounds enter tumor cells, the activities of TS, glycinamide ribonucleotide formyl transferase (GARFTase) and 5-amino imidazole-4-carboxamide ribonucleotide formyl transferase (AICARFTASE) can be simultaneously inhibited, and the synthesis of thymine nucleotide and purine nucleotide required by DNA synthesis is blocked from multiple ways, so that the DNA synthesis of the tumor cells is blocked, and the apoptosis of the tumor cells is finally induced. In addition, the