Search

CN-122011090-A - Protein degradation targeting chimeric body targeting FGFR4 as well as preparation method and application thereof

CN122011090ACN 122011090 ACN122011090 ACN 122011090ACN-122011090-A

Abstract

The invention discloses a protein degradation targeting chimeric body targeting FGFR4 and a preparation method and application thereof, and relates to the technical field of biological medicines. The protein degradation targeting chimeric has a structure shown in a formula (V1), is formed by coupling a covalent inhibitor ligand of targeting FGFR4 and an E3 ubiquitin ligase ligand through a linker, constructs an intermediate through multi-step organic synthesis and finally obtains a target compound through an amide condensation reaction, and can specifically bind and induce the ubiquitination degradation of FGFR4 protein, so that the protein degradation targeting chimeric has a remarkable curative effect in preparing the FGFR 4-mediated tumor treatment drug. In the development of FGFR4 targeted proteolytic chimera, a lead compound with potential is provided for the first time, and the problem that the FGFR4 protein targeted chimera is never used as the reference is solved.

Inventors

  • LONG RUI
  • LI YUEHUI

Assignees

  • 重庆医科大学

Dates

Publication Date
20260512
Application Date
20260203

Claims (9)

  1. 1. A protein degradation targeting chimera targeting FGFR4, wherein the protein degradation targeting chimera has a structure according to formula (V1): The chemical name is (2S, 4R) -1- ((R) -2- (2- (4- (3-acrylamido-4- ((6- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-methylureido) pyrimidin-4-yl) amino) phenyl) piperazin-1-yl) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide.
  2. 2. The FGFR 4-targeted protein degradation targeting chimera of claim 1, further comprising a pharmaceutically acceptable salt of the protein degradation targeting chimera selected from the group consisting of hydrochloride, sulfate, phosphate, mesylate, citrate, maleate, fumarate, and tartrate.
  3. 3. A method of making a FGFR4 targeted protein degradation targeting chimera of claim 1, comprising the steps of: Performing an amide condensation reaction on an intermediate compound shown in a formula (11) and (2S, 4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide under the action of a condensation reagent and a base to prepare a protein degradation targeting chimeric shown in the formula (V1); The intermediate compound shown in the formula (11) has the following structure: The chemical name of the compound is 2- [4- (3-acrylamide-4- ((6- (3- (2, 6-dichloro-3, 5-dimethoxy phenyl) -1-methyl ureido) pyrimidine-4-yl) amino) phenyl) piperazine-1-yl ] acetic acid.
  4. 4. A process according to claim 3, wherein the condensing agent is selected from one or more of HATU, EDCI, DCC or T3P and the base is selected from one or more of DIEA, triethylamine, pyridine or 4-dimethylaminopyridine.
  5. 5. A method according to claim 3, further comprising the step of preparing an intermediate compound represented by the formula (11): The intermediate compound shown in the formula (9) and tert-butyl bromoacetate are subjected to substitution reaction under alkaline conditions to prepare an intermediate compound shown in the formula (10), and then the intermediate compound shown in the formula (10) is hydrolyzed under acidic conditions to obtain the intermediate compound shown in the formula (11); Wherein the structural formulas of the formula (9) and the formula (10) are as follows: 。
  6. 6. use of a FGFR4 targeted protein degradation targeting chimera according to claim 1 for the preparation of a medicament for the treatment of tumors, characterized in that the tumors are FGFR4 mediated tumors.
  7. 7. The use according to claim 6, wherein the FGFR4 mediated tumor is selected from hepatocellular carcinoma.
  8. 8. The use according to claim 7, wherein the medicament acts to induce apoptosis in tumor cells by down-regulating the expression level of FGFR4 protein in tumor cells.
  9. 9. The use according to claim 8, wherein the tumor cell is a hepatocellular carcinoma JHH-7 cell overexpressing FGFR 4.

Description

Protein degradation targeting chimeric body targeting FGFR4 as well as preparation method and application thereof Technical Field The invention relates to the technical field of biological medicine, in particular to a protein degradation targeting chimeric body targeting FGFR4, and a preparation method and application thereof. Background Fibroblast growth factor receptor 4 (Fibroblast Growth Factor Receptor, FGFR 4) is a receptor tyrosine kinase, belongs to the fibroblast growth factor receptor family, and plays a key role in maintaining physiological processes such as metabolic homeostasis, tissue development and the like of a human body. Studies show that the FGF19/FGFR4 signal channel abnormal activation caused by FGFR4 gene amplification, point mutation or gene fusion is closely related to the occurrence and development of various malignant tumors, and particularly has remarkable manifestation in hepatocellular carcinoma, breast cancer and colorectal cancer. Therefore, targeting FGFR4 has become an important strategy for the clinical treatment of such dependent cancers. Currently, therapies directed to FGFR4 have focused mainly on the development of small molecule inhibitors such as BLU9931, H3B-6527, FGF401, and the like. These compounds inhibit FGFR4 activity by competitively binding to the ATP binding site of the kinase domain, and are now partially entered into the clinical trial phase. However, with the penetration of clinical studies, the limitations of conventional small molecule inhibitors are increasingly prominent. Firstly, long-term use of tyrosine kinase inhibitors often results in acquired resistance, which is often associated with secondary mutations of the target protein, and secondly, to achieve adequate inhibition, higher doses are often required, which may cause serious toxic side effects and safety problems. Furthermore, for some non-enzymatically active stent functions, simple inhibition of activity tends to be difficult to completely block tumor progression. In recent years, protein degradation targeting chimera technology is used as a novel drug development strategy, and targeted degradation of target proteins is realized by using an ubiquitin-protease system by recruiting E3 ubiquitin ligase to the vicinity of the target proteins. Compared with the traditional inhibitor, the protein degradation strategy has catalytic cycle characteristics, can thoroughly remove target proteins at a lower concentration, and is expected to overcome drug resistance mutation and improve targeting selectivity. Although there have been many studies on such compounds for other targets, in the FGFR4 field, there is still a lack of maturation protocols that can compromise efficient degradation, covalently stable binding, and significant induction of tumor cell apoptosis. Therefore, the novel, efficient and good pharmacological activity FGFR4 protein degradation agent is developed, and has important clinical significance and scientific research value for improving the treatment effect of FGFR4 mediated diseases such as hepatocellular carcinoma and the like. Disclosure of Invention The invention provides a target FGFR4 protein degradation target chimeric body, a preparation method and application thereof, and provides a lead compound with potential for the first time in the development of the FGFR4 target proteolytic chimeric body, thereby solving the problem that the FGFR4 protein target chimeric body is free from existence. In a first aspect, an embodiment of the present invention provides a protein degradation targeting chimera targeting FGFR4, the protein degradation targeting chimera having a structure according to formula (V1): The chemical name is (2S, 4R) -1- ((R) -2- (2- (4- (3-acrylamido-4- ((6- (3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1-methylureido) pyrimidin-4-yl) amino) phenyl) piperazin-1-yl) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide. Preferably, it also comprises a pharmaceutically acceptable salt of the protein degradation targeting chimera, the pharmaceutically acceptable salt being selected from the group consisting of hydrochloride, sulfate, phosphate, mesylate, citrate, maleate, fumarate or tartrate. In a second aspect, an embodiment of the present invention provides a method for preparing the FGFR4 targeting protein degradation targeting chimera according to the previous embodiment, comprising the following steps: Performing an amide condensation reaction on an intermediate compound shown in a formula (11) and (2S, 4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-formamide under the action of a condensation reagent and alkali to prepare a protein degradation targeting chimeric shown in a formula (V1); The intermediate compound represented by formula (11) has the following structure: The chemical name of the compound is 2- [4- (3-ac