Proteolysis targeting chimeric body, prodrug molecule for improving oral bioavailability of protein hydrolysis targeting chimeric body and application thereof

A technology of proteolysis and chimera, applied in the field of chemistry, can solve the problems of inability to degrade CDK2 and apoptosis of cancer cells at the same time, and achieve the effect of facilitating animal experiments

Active Publication Date: 2020-11-10
DONGGUAN UNIV OF TECH
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Problems solved by technology

[0008] The present invention aims at the technical defects of the prior art, and provides a proteolytic targeting chimera, a prodrug molecule and its application to improve i

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  • Proteolysis targeting chimeric body, prodrug molecule for improving oral bioavailability of protein hydrolysis targeting chimeric body and application thereof
  • Proteolysis targeting chimeric body, prodrug molecule for improving oral bioavailability of protein hydrolysis targeting chimeric body and application thereof
  • Proteolysis targeting chimeric body, prodrug molecule for improving oral bioavailability of protein hydrolysis targeting chimeric body and application thereof

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Embodiment Construction

[0056] Specific embodiments of the present invention will be described in detail below. In order to avoid too many unnecessary details, well-known structures or functions will not be described in detail in the following embodiments. Approximate language used in the following examples is for quantitative representations, indicating that certain variations in quantities are permissible without altering essential function. Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0057] 1. PROTAC molecular design and synthesis of compound 3

[0058] The structure of ribociclib1 is considered to be the binding part of CDKs because of its high binding capacity for CDK4 / 6. However, ribociclib1 has no inhibitory effect on CDK2. A great deal of effort has gone into synthesizing and screening suitable analogs. Fortunately, core structure ...

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Abstract

The invention provides a proteolytic targeting chimeric body, a prodrug molecule for improving oral bioavailability of the proteolytic targeting chimeric body and application thereof. According to thetechnical scheme, a novel PROTAC degradation agent compound is developed on the basis of a ribociclib derivative and a CRBN ligand. Small molecules can effectively degrade CDK2/4/6 and compounds thereof in malignant melanoma at the same time; the cell cycle can be quickly reset, and apoptosis of various cancer cells, especially melanoma cells, can be induced. A mechanism should be explained as that CDK 2/4/6 deficiency may lead to synthetic lethal effects of malignant melanoma in the presence of a compound. The results show that the combination of CDK2/4/6 is expected to become a kinase target for treating solid tumors. In addition, the invention also develops a prodrug with high oral bioavailability for the first time, and is convenient for oral administration in animal tests. A universal solution is provided for oral administration of PROTAC molecules with CRBN ligands.

Description

technical field [0001] The invention relates to the field of chemical technology, and further relates to chemical synthesis technology and medicinal chemistry technology, in particular to a proteolysis-targeted chimera, a prodrug molecule for improving its oral bioavailability and its application. Background technique [0002] Cyclin-dependent kinases (CDKs) are key cellular enzymes that regulate eukaryotic cell division and cell proliferation. The catalytic units of CDKs are activated by regulatory subunits, cyclins. So far, 16 mammalian cell cycle proteins have been identified, among which Cyclin B / CDK1, Cyclin A / CDK2, Cyclin E / CDK2, Cyclin D / CDK4 and Cyclin D / CDK6 are important regulators of cell cycle progression. Other functions of cyclins / CDKs (such as transcriptional regulation, DNA repair, differentiation, and apoptosis) have also been reported. [0003] The enhanced or temporarily abnormal activation of CDKs leads to the occurrence of various tumors. Therefore, c...

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Application Information

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IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04A61P35/00
Inventor 王晓季杨陈阳张学松郭文彬陈新
Owner DONGGUAN UNIV OF TECH
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