Inhibitor for targeted tumor cell surface PD-L1 molecules and application thereof

Abstract

The invention provides an inhibitor for targeted tumor cell surface PD-L1 molecules and an application thereof. The invention utilizes an Odyssey On / In Cell Western Blot screening system to find thatcompounds Cobimetinib (GDC-0973, RG7420), AT7519, Lapatinib, LY2090314 and KU-60019 are capable of showing an effect of excellently restraining PD-L1 expression in different cell experiments under a low cytotoxicity condition, and the inhibiting effect has been verified in two different types of tumor cells. Thus, these compounds (especially KU-60019) are expected to be developed into small-molecule inhibitors for clinically inhibiting PD-L1 expression. Besides, a corresponding kinase thereof also becomes a pharmacological target for researching PD-1 / PD-L1 signal channels.

Description

technical field [0001] The invention relates to the field of tumor immunotherapy, in particular to an inhibitor targeting PD-L1 molecules on the surface of tumor cells and its application. Background technique [0002] In the immune regulation of the body, various checkpoint molecules play a complex immune regulatory role. There are many types of these molecules, such as PD-1, CTLA-4, IDO, TIM3, etc. Among them, the programmed death receptor (PD-1) has received the most attention in current clinical research, and has been successfully applied clinically, which has greatly promoted the progress of tumor immunotherapy. PD-1 has two ligands - programmed death ligand 1 (PD-L1) and programmed death receptor ligand 2 (PD-L2), PD-L1 or PD-L2 binds to PD-1, and is stimulated by antigen Receptor signal transduction phosphorylates two tyrosine signaling motifs in the cytoplasmic region of PD-1, thereby activating downstream signaling pathways, and ultimately destroying the glucose me...

AI Technical Summary

Problems solved by technology

[0004] Although monoclonal antibodies targeting the PD-1 / PD-L1 / PD-L2 signaling pathway have been highly valued and breakthroughs continue to emerge, due to the high cost of research and development, harsh transportation and storage conditions, and the stability of antibody drugs In recent years, many researchers have expanded the inhibitors targeting the PD-1 / PD-L1 / PD-L2 signaling pathway to the field of traditional small molecule drugs, checkpoint proteins Small molecule inhibitors are receiving increasing attention

At present, there are small molecule inhibitors targeting the PD-1 / PD-L1 / PD-L2 signaling pathway in phase I clinical stage, but no small molecule compound has been approved for marketing so far

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