Search

CN-121991034-A - Compound targeting FAK degradation and application

CN121991034ACN 121991034 ACN121991034 ACN 121991034ACN-121991034-A

Abstract

The invention discloses a compound for targeting FAK degradation and application thereof, which have a structure shown in a formula (I) and can be used for preparing a medicament for treating, preventing and relieving diseases caused by excessive FAK protein expression. The PROTAC compounds for targeted degradation of FAK protein have the capability of obviously degrading FAK in MIA-PACA-2 cells at different concentrations, and the combination of KRAS inhibitor has a certain proliferation inhibition capability on MIA-PACA-2 cells. Can be developed as a potential anti-solid tumor drug, and has wide application prospect.

Inventors

  • HUANG WENHAI
  • ZENG SHENXIN
  • WU MINGFEI
  • ZHENG HONGMEI
  • ZHU YINGCHEN
  • WANG ZUNYUAN

Assignees

  • 杭州医学院

Dates

Publication Date
20260508
Application Date
20260120

Claims (9)

  1. 1. A compound targeting FAK degradation, characterized by a structure represented by formula (I): ; Wherein, the R1 is-CF 3 or-Cl; linker is a connecting chain, and the structure is: 。
  2. 2. The compound targeting FAK degradation of claim 1, which is a compound of the structure: Compound 1: ; Compound 2: ; compound 3: ; compound 4: ; Compound 5: ; compound 6: ; compound 7: ; Compound 8: ; compound 9: ; Compound 10: ; Compound 11: 。
  3. 3. Use of a compound targeting FAK degradation according to claim 1 or 2 for the preparation of a medicament for the treatment, prevention and alleviation of diseases caused by overexpression of FAK protein.
  4. 4. The use of stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, and pharmaceutically acceptable salts thereof of a compound targeted to FAK degradation according to claim 1 or 2 for the preparation of a medicament for the treatment, prevention and alleviation of diseases caused by excessive expression of FAK protein.
  5. 5. The use according to claim 3 or 4, wherein the disease caused by excessive expression of FAK protein is cholangiocarcinoma, diffuse large B-cell lymphoma, renal clear cell carcinoma, low grade glioma, sarcoma, thymoma, mesothelioma, meningioma, gastric adenocarcinoma, melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, renal cancer, head and neck cancer, pheochromocytoma or paraganglioma.
  6. 6. Use of a compound targeting FAK degradation according to claim 1 or 2 for the preparation of a medicament for the treatment of pancreatic cancer.
  7. 7. The use of stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites and pharmaceutically acceptable salts thereof of a compound targeted to FAK degradation according to claim 1 or 2 for the preparation of a medicament for the treatment of pancreatic cancer.
  8. 8. Use of a compound targeting FAK degradation according to claim 1 or 2 for the preparation of a medicament in combination with a KRAS inhibitor.
  9. 9. The use of stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, and pharmaceutically acceptable salts thereof of a compound targeted to FAK degradation according to claim 1 or 2 for the preparation of a medicament in combination with a KRAS inhibitor.

Description

Compound targeting FAK degradation and application Technical Field The invention relates to the field of chemical synthesis, in particular to a compound for targeting FAK degradation and application thereof. Background Focal Adhesion Kinase (FAK), also known as PTK2 (protein tyrosine kinase 2), is a non-receptor type protein tyrosine kinase that is widely expressed in various tissues of the human body, and is mainly regulated by integrin signals, and controls basic cell processes of cell adhesion, migration, proliferation and survival through kinase-dependent and kinase-independent functions. FAK consists of FERM domain, kinase domain, proline rich region and FAT domain. The various domains of FAK make it a core scaffold for cellular signaling complexes, capable of binding to multiple proteins simultaneously, forming highly dynamic signaling complexes, which in turn integrate extracellular matrix (Extracellular matrix, ECM) signaling precisely into intracellular signaling pathways. During this process, binding of integrins to extracellular matrix recruits FAK to the focal adhesion and initiates trans autophosphorylation at the Y397 site. Once phosphorylated, FAK acts as a molecular scaffold and recruits Src Family Kinase (SFKs) to bind to FAK, activating its catalytic function, causing further phosphorylation of multiple tyrosine residues of FAK, thereby enhancing its function as a scaffold protein, and activating multiple downstream signaling pathways, such as PI3K-AKT pathway, ras-MAPK pathway, STAT1 pathway, and the like. Activation of these signaling pathways plays a vital role in the growth, proliferation, metastasis, invasion, etc. of tumor cells. In addition, the overexpression of FAK is also associated with chemotherapy resistance and radiotherapy resistance of cancer, and inhibition of FAK signaling pathways can reverse tumor resistance and enhance immunotherapeutic effects. Thus, inhibition or degradation of FAK is considered a new strategy in cancer treatment. Although many FAK inhibitors have achieved good results in preclinical or clinical trials, particularly in refractory tumors such as platinum-resistant ovarian and pancreatic cancers, it is noted that no small molecule inhibitors that directly target FAK have been clinically approved worldwide. In addition, small molecule inhibitors of FAK target primarily the kinase active region of FAK without disrupting scaffold function, only partially blocking its signaling function. This limitation of selective inhibition often results in tumor cells becoming resistant to drugs through activation of non-kinase domain signaling pathways. This makes the strategy of kinase inhibition alone a major limitation in the clinical application of targeted FAK during treatment. The proteolytic targeting chimera (Proteolysis TARGETING CHIMERA, PROTAC) technology has received great attention as an innovative drug development strategy. The PROTAC technology is that PROTAC molecules are used for connecting target proteins and E3 ubiquitin ligase, so that ternary complexes of target proteins-PROTAC-E3 ubiquitin ligase are formed, and the target proteins are ubiquitinated by the E3 ligase. The ubiquitinated proteins can be specifically recognized and degraded by the proteasome within the cell. Compared with the traditional inhibitor which can only inhibit a single signal path of some multifunctional proteins, PROTAC molecules can induce the degradation of target proteins so as to influence all functions of the proteins, thereby reducing feedback mechanisms, overcoming drug resistance and reducing the occurrence probability of drug resistance to a certain extent. In addition, PROTAC has the potential advantages of low dosage, low toxicity, capability of overcoming drug resistance, improving selectivity, targeting non-patentable proteins and the like, and the breakthrough advantages make PROTAC technology the protein degradation treatment strategy with the most clinical transformation potential at present. Therefore, there is a need to develop PROTAC class of compounds that target the degradation of FAK proteins. Disclosure of Invention The invention aims to provide a compound targeting FAK degradation and application thereof. The PROTAC compounds for targeted degradation of FAK protein have the capability of obviously degrading FAK in MIA-PACA-2 cells at different concentrations, and the combination of KRAS inhibitor has a certain proliferation inhibition capability on MIA-PACA-2 cells. Can be developed as a potential anti-solid tumor drug, and has wide application prospect. In order to achieve the above purpose, the present invention provides a compound PROTAC for degrading FAK protein, which has the structure of formula I: wherein Linker is a connecting chain connected to the 4-position of the right isoindole-1, 3-dione structure, and has the structure: ; Wherein R1 is a group of-CF 3 or-Cl. Further, the PROTAC compound for degrading the FAK protein, or a stereoisomer