Discovery of novel BTK PROTACs with improved metabolic stability via linker rigidification strategy

Bruton's Tyrosine Kinase (BTK) functions as a key regulator of B-cell receptor (BCR) signaling pathway, which is frequently hyperactivated in a variety of lymphoma cancers. Using Proteolysis Targeting Chimera (PROTAC) technology, we have recently discovered a highly potent ARQ-531-derived BTK PROTAC 6e, inducing effective degradation of both wild type (WT) and C481S mutant BTK proteins. However, the poor metabolic stability of PROTAC 6e have limited its further in vivo studies. Herein, we present our structure-activity relationship (SAR) studies on modifying PROTAC 6e using linker rigidification strategy to identify a novel cereblon (CRBN)-recruiting compound 3e that induced BTK degradation in a concentration-dependent manner but had no effect on reducing the level of CRBN neo-substrates. Moreover, compound 3e suppressed the cell growth more potently than the small molecule inhibitors ibrutinib and ARQ-531 in several cells. Furthermore, compound 3e with the rigid linker displayed a significantly improved metabolic stability profile with the T1/2 increased to more than 145 min. Overall, we discovered a highly potent and selective BTK PROTAC lead compound 3e, which could be further optimized as potential BTK degradation therapy for BTK-associated human cancers and diseases.