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CN-122010936-A - Multi-kinase inhibitor, PROTACs target protein ligand, and synthesis method and application thereof

CN122010936ACN 122010936 ACN122010936 ACN 122010936ACN-122010936-A

Abstract

The invention discloses a multi-kinase inhibitor, PROTACs target protein ligand, a synthesis method and application thereof, wherein the multi-kinase inhibitor is a compound with a structure shown in a formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, has kinase inhibition activities of mixed lineage kinase 3 (MLK 3), FMS-like tyrosine kinase 3 (FLT 3), hematopoietic progenitor cell kinase 1 (HPK 1) and the like, and is used for developing protein degradation chimeric (PROTACs) targets, a preparation method and application thereof, and the compound can inhibit the activities of MLK3, FLT3 and HPK1 and is used for developing PROTACs and is used for treating various diseases including cancers, immunoregulation, autoimmunity and the like. (I)。

Inventors

  • DONG JIAHANG
  • ZENG SHENXIN
  • XU YUXI
  • ZHENG HONGTAO
  • CHEN XINYI
  • HUANG WENHAI

Assignees

  • 杭州医学院

Dates

Publication Date
20260512
Application Date
20260126

Claims (7)

  1. 1. A multi-kinase inhibitor characterized by a compound having a structure according to formula (I): ; (I) Wherein: r 1 is selected from one of the following structures: ; R 2 is selected from one of the following structures: 。
  2. 2. The multi-kinase inhibitor according to claim 1, which is a compound of the structure: 、 、 、 。
  3. 3. A PROTACs target protein ligand, characterized by being a compound of the structure: 、 、 、 。
  4. 4. The method of synthesis of a multi-kinase inhibitor according to claim 1 or 2, comprising the steps of: (1) Reacting a compound of formula A with a compound of formula B under the catalysis of a transition metal to produce a compound of formula C; ; formula A, formula B and formula C; (2) Reacting a compound of formula C with a compound of formula D under transition metal catalysis to produce a compound of formula (I); ; a formula D; Wherein R 1 in the formula B and the formula C are consistent with R 1 in the formula (I), and R 2 in the formula D is consistent with R 2 in the formula (I).
  5. 5. Use of a multi-kinase inhibitor according to claim 1 or 2 in the manufacture of a medicament for the prevention or treatment of a disease caused by overexpression of MLK3, FLT3, HPK 1.
  6. 6. The use according to claim 5, wherein the multi-kinase inhibitor is used alone or in combination with a pharmaceutically acceptable excipient or carrier in the medicament.
  7. 7. The use according to claim 5, wherein the disease caused by the overexpression of MLK3, FLT3, HPK1 is breast cancer, parkinson's disease, alzheimer's disease, amyotrophic lateral sclerosis, ovarian cancer, cervical cancer, prostate cancer, glioblastoma or hematological tumor.

Description

Multi-kinase inhibitor, PROTACs target protein ligand, and synthesis method and application thereof Technical Field The invention relates to the field of small molecule medicines, in particular to a novel kinase inhibitor, and particularly provides a compound which has kinase inhibition activities of mixed lineage kinase 3 (MLK 3), FMS-like tyrosine kinase 3 (FLT 3), hematopoietic progenitor cell kinase 1 (HPK 1) and other kinases and is used for developing a target head of a protein degradation chimeric body (PROTACs), synthesis and application thereof. Background Protein kinase is used as a core regulatory factor for cell signal transduction, and key biological functions such as cell proliferation, differentiation, apoptosis and immune response are accurately regulated by catalyzing the phosphorylation process of substrate proteins. Abnormal activation or deregulation of expression thereof is closely associated with a variety of major diseases including cancer, autoimmune diseases and chronic inflammation. Currently, small molecule kinase inhibitors have become the dominant strategy for drug development, and representative drugs such as imatinib (for chronic myeloid leukemia) and gefitinib (for non-small cell lung cancer) have successfully achieved clinical transformations. However, the traditional inhibitors only can block the catalytic activity by reversibly or irreversibly combining with kinase ATP binding pocket, and have remarkable limitations that on one hand, target proteins are not cleared and drug resistance is easily caused by activation of compensatory signal channels or over-expression of targets, and on the other hand, the insufficient selectivity of the inhibitors is easy to cause off-target toxicity, so that long-term curative effect and application range are limited. Among the many kinase targets, mixed lineage kinase 3 (MLK 3), FMS-like tyrosine kinase 3 (FLT 3), and hematopoietic progenitor kinase 1 (HPK 1) have been of interest for their key role in disease. MLK3 belongs to serine/threonine kinase of MAPK signal pathway, and participates in regulating JNK/p38 pathway, and plays an important role in tumor metastasis, neurodegenerative diseases and inflammatory reaction. Studies show that MLK3 is highly expressed in solid tumors such as breast cancer, colorectal cancer and the like, promotes cancer cell invasion and chemotherapy resistance, but no high-efficiency specific inhibitor enters clinic at present. FLT3 is a hematopoietic specific receptor tyrosine kinase whose internal tandem repeat (ITD) mutations account for 25-30% of Acute Myeloid Leukemia (AML) patients, and is a central driver leading to disease recurrence and poor prognosis. Although FLT3 inhibitors such as midostaurin and gelitinib have been approved for AML treatment, the rapid onset of drug resistant mutations (such as FLT 3-TKD) has compromised efficacy. HPK1 as MAP4K family member is the negative regulator of T cell receptor signal channel, and its activity inhibition can eliminate inhibition of T cell and strengthen antitumor immune response. In tumor microenvironments, high expression of HPK1 is associated with immune escape, inhibitors targeting HPK1 (e.g., HPK1 i-1) have demonstrated potential in immunotherapy, but their single-target effects are difficult to cover complex disease mechanisms. In view of the above challenges, the protein degradation targeting chimera (PROTACs) technology provides a revolutionary idea for kinase targeting therapy. PROTACs through bifunctional molecule design, one end targets target Protein (POI), and the other end recruits E3 ubiquitin ligase to induce POI ubiquitination and degradation by proteasome, thereby realizing the treatment target of eliminating target protein instead of inhibiting activity. Compared with the traditional inhibitor, PROTACs has the advantages of catalysis (POI can be degraded by single molecule for many times), high selectivity and targeting of 'non-patent medicine' proteins. In the kinase field, PROTACs has been successfully applied to target points such as BTK (such as ARV-471), BRD4 (such as AZD 5153) and the like, thereby remarkably improving the curative effect and overcoming the drug resistance. However, PROTACs is highly dependent on the quality of the targeting ligand (warhead), i.e., it is desirable to meet both (1) high affinity binding to the target kinase, (2) retention of chemical modification sites to be linker-E3 ligand binding and (3) no impact on protein degradation efficiency. At present, PROTACs target researches on MLK3, FLT3 and HPK1 are seriously insufficient, namely, in the prior literature, an MLK3 inhibitor (such as CEP-1101) lacks PROTACs compatible structures, an FLT3 inhibitor (such as Quizartinib) is mostly ATP competitive molecules and is difficult to optimize into a degradation agent, and an HPK1 inhibitor (such as GSK 225602) focuses on immunoregulation and is not explored for PROTACs application. More critical, the lack of co