Targeted selective degradation of Bruton’s tyrosine kinase by PROTACs

Abstract

Bruton’s tyrosine kinase (BTK) is critical for B-cell receptor signaling and related to many types of human cancers. However, the drug resistance and off-target effect of present traditional BTK inhibitors occurred over time. As a new strategy for drug development, the proteolysis targeting chimera (PROTAC) has been proved to target varieties of proteins. Here SPB5208 (4-(2-(2-(2-(2-(3-(4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) was synthesized as a new PROTAC degradation agent of BTK by linking Ibrutinib and Thalidomide. In vitro study indicated that SPB5208 reduced the BTK enzyme activity with high selectivity and inhibited effectively cancer cell proliferation. More than that, SPB5208 induced BTK protein degradation through a proteasome- and CRBN- dependent manner in JeKo-1 cells. In addition, SPB5208 was also confirmed to induce significantly BTK protein degradation in vivo. Thus, this study provides a new pharmacological tool for further study of new BTK PROTAC and their mechanism of action in physiological environment.