CN-122010844-A - Synthesis and application of AR protein degradation agent

CN122010844ACN 122010844 ACN122010844 ACN 122010844ACN-122010844-A

Abstract

The invention relates to the technical field of pharmaceutical chemistry, in particular to synthesis and application of an AR protein degradation agent; the AR protein degradation agent modified by using norbornene, adamantanecarboxylic acid and adamantaneacetic acid as hydrophobic labels can effectively inhibit proliferation of tumor cells, induce androgen protein degradation, and is dose-dependent and time-dependent, the compound can enable target protein to be identified by ubiquitin ligase without affecting combination of target protein ligand and receptor by changing chain length, the preferred protein degradation agent obtained by the invention uses norbornene as hydrophobic labels, the groups of the preferred protein degradation agent are smaller than that of adamantanecarboxylic acid and adamantaneacetic acid as hydrophobic label groups, the parent nucleus of the AR protein degradation agent compound is paired with AR protein, inhibition effect on tumors is superior to that of the prior AR inhibitor enzalutamide by using the hydrophobic labels, the preparation steps of the compound are less, the purification method is simple, and the yield is high.

Inventors

ZHANG XINGTING
XU SHENGTAO
XIE SHAOWEN
WANG XINYI
JIANG WEI
CHEN XIA
LIN XIANG

Assignees

中国药科大学

Dates

Publication Date: 20260512
Application Date: 20260317

Claims (8)

1. An AR protein degrading agent, a pharmaceutically acceptable salt thereof, characterized in that the AR protein degrading agent consists of a hydrophobic tag molecule and a parent nucleus; the parent nucleus is of a structure shown in a formula I, and the hydrophobic tag molecule comprises structures shown as B1, B2 and B3; A formula I; ; Where n=1, 2,3.
2. The AR protein degradation agent, pharmaceutically acceptable salt thereof, according to claim 1, wherein the molecular structure of the AR protein degradation agent comprises the structure shown in the following J1, J2, J3, J4, J5, J6, J7, J8, J9; 。
3. The AR protein degrading agent, pharmaceutically acceptable salt thereof according to claim 2, wherein the molecular structure of the AR protein degrading agent is shown as J2; 。
4. A method for preparing an AR protein degrading agent, a pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein the preparation route is as follows: ; ; ; 。
5. use of an AR protein degrading agent according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with abnormal expression of AR protein.
6. The use according to claim 5, wherein the disease associated with abnormal expression of AR protein comprises prostate cancer, renal cancer, breast cancer.
7. Use of an AR protein degrading agent according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer associated with abnormal expression of AR protein.
8. The use according to claim 7, wherein the cancer associated with abnormal expression of AR protein comprises prostate cancer, renal cancer, breast cancer.

Description

Synthesis and application of AR protein degradation agent Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to synthesis and application of an AR protein degradation agent. Background The incidence of prostate cancer (PCa) is in front of global male malignancies. And shows a trend of growing year by year. Aberrant activation of androgen receptor (androgen receptor, AR) is closely related to the development of PCa. AR consists of four functional domains, an amino terminal domain (NTD), a DNA-binding domain (DBD), a finger domain (HD), and a carboxy terminal ligand domain (ligand binding domain, LBD). NTD is responsible for the transcriptional activation of AR, and when NTD is mutated or amplified, the transcriptional activation ability of AR can be enhanced, and LBD and androgen are combined to promote AR dimerization and enter cell nucleus, up-regulate the expression of pro-proliferation genes, inhibit apoptosis and lead to malignant proliferation of cells. Existing therapeutic agents inhibit tumor cell growth by blocking androgen binding to AR. However, the conventional antagonists have problems of drug resistance, and the blocking of the antagonists is not complete, so that the therapeutic effect is not ideal. The protein degradation agent can degrade pathogenic proteins, fundamentally eliminate pathogenic factors, is hopeful to overcome the drug resistance problem, and provides a solution for some targets difficult to prepare. The currently common protein degradation mode is PROTAC (target protein degradation chimeric), but the defects of large molecular weight, poor drug formation and the like exist. The hydrophobic tag protein degrading agent is designed by attaching a hydrophobic tag (e.g., adamantane, norbornene, etc.) to the linker chain and then to the target protein ligand. The hydrophobic tag has smaller molecular weight and better pharmacy, and can become a protein degradation mode better than PROTAC. The design of hydrophobic tag protein degradation agents relies on a large number of molecular syntheses and tests, and small differences in the different linking chains, hydrophobic tags and modes of attachment can have a significant impact on protein degradation activity. Therefore, the design and synthesis of the hydrophobic tag protein degradation agents with different types and different connecting chains are expected to find out the protein degradation agents with better activity and better patent medicine property, and a more preferable scheme is provided for the treatment of the prostate cancer. Disclosure of Invention The invention aims to provide an AR protein degradation agent with excellent protein degradation capability and anti-tumor activity, which is realized by a double-function hydrophobic label, and the protein degradation agent can overcome the problems of incomplete drug resistance, incomplete blocking and the like of an antagonist by degrading the AR, is hopeful to become an effective means for treating the prostate cancer, and provides a new design thought for developing medicaments for the prostate cancer so as to solve the problems in the background technology. In order to achieve the above purpose, the present invention provides the following technical solutions: The invention provides an AR protein degradation agent and pharmaceutically acceptable salt thereof, wherein the AR protein degradation agent consists of a hydrophobic tag molecule and a mother nucleus; The parent nucleus has a structure shown in a formula I, and the hydrophobic tag molecule comprises a structure shown in B1 (norbornene), B2 (adamantanecarboxylic acid) and B3 (adamantaneacetic acid); A formula I; ; The structural general formula of the AR protein degradation agent is shown in the following formula II: Formula II. Where n=1, 2,3. R is、Or (b)。 Further, the molecular structure of the AR protein degradation agent comprises the following structures shown in J1, J2, J3, J4, J5, J6, J7, J8 and J9; 。 preferably, the molecular structure of the AR protein degrading agent is shown as J2; 。 The preparation method of the AR protein degradation agent and the pharmaceutically acceptable salt thereof is as follows: ; ; ; 。 The application of the AR protein degradation agent and the pharmaceutically acceptable salt thereof in preparing the medicine for treating the diseases related to the abnormal expression of the AR protein. Further, the diseases associated with abnormal expression of the AR protein include prostate cancer, renal cancer, and breast cancer. The application of the AR protein degradation agent and the pharmaceutically acceptable salt thereof in preparing the medicine for treating the cancers related to abnormal expression of the AR protein. Further, cancers associated with abnormal expression of the AR protein include prostate cancer, renal cancer, breast cancer. Compared with the prior art, the invention has the beneficial effects that: The inv