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

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, further relates to chemical synthesis technology and medicinal chemistry technology, and specifically relates to a proteolytic targeting chimera, a prodrug molecule that improves 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. Currently, 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] Enhanced activity or temporary abnormal activation of CDKs leads to the occurrence of various tumors...

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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 its oral bioavailability, so as to solve the problem that current PROTAC molecules cannot simultaneously degrade CDK2 / 4 / 6 and induce Technical Issues of Cancer Cell Apoptosis

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