Proteolysis targeting chimera and application thereof

Abstract

The invention provides a proteolysis targeting chimera and application thereof. According to a technical scheme in the invention, a novel PROTAC degradation agent compound 21a is developed on the basis of a BMS-37 small molecule. The novel PROTAC degradation agent compound 21a is an example of degrading membrane proteins on the basis of a ligand binding to the extracellular domain of a PD-L1 protein, and can effectively degrade PD-L1 in various malignant tumor cells. In-vivo research results show that after treatment with the compound 21a, the compound 21a can significantly reduce the level of the PD-L1 in tumors, promote infiltration of CD8<+>T cells and significantly inhibit growth of mouse colorectal cancer MC-38 cells. The PROTAC molecule is expected to be one of novel and alternative strategies for cancer immunotherapy.

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 targeting chimera and its application. Background technique [0002] Immune checkpoints refer to those interactions that inhibit the activation of CTLs (cytotoxic T lymphocytes, also known as killer T cells). These checkpoints are a natural design of the immune response, acting as "brakes" for CTLs, allowing CTL activation for a period of time but not allowing the response to proceed indefinitely, one of the many regulatory mechanisms of the immune response. Immune checkpoint therapy has attracted increasing attention, and inhibition of the programmed cell death receptor 1 (PD-1) / programmed cell death ligand 1 (PD-L1) interaction is one of the most promising strategies. [0003] Numerous clinical trials have proved that immune checkpoint blocking antibody drugs targeting PD-1...

AI Technical Summary

Problems solved by technology

However, there are very limited reports on GPCR degradation (e.g., FLT3)

It is worth noting that most of the reported PROTACs are designed through the structure of ligands that bind to the intracellular domain of target proteins, however, few reports have found ligands that bind to the intracellular domain of PD-L1.

Therefore, this becomes an important challenge in designing PROTAC molecules targeting PD-L1

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