Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy

Bruton's tyrosine kinase (BTK) is a target fortreatingB-cell malignancies and autoimmune diseases, and several BTK inhibitorsare already approved for use in humans. Heterobivalent BTK proteindegraders are also in development, based on the premise that proteolysistargeting chimeras (PROTACs) may provide additional therapeutic benefits.However, most BTK PROTACs are based on the BTK inhibitor ibrutinibraising concerns about their selectivity profiles, given the knownoff-target effects of ibrutinib. Here, we disclose the discovery and in vitro characterization of BTK PROTACs based on the selectiveBTK inhibitor GDC-0853 and the cereblon recruitment ligandpomalidomide. PTD10 is a highly potent BTK degrader (DC50 0.5 nM) that inhibited cell growth and induced apoptosisat lower concentrations than the two parent molecules, as well asthree previously reported BTK PROTACs, and had improved selectivitycompared to ibrutinib-based BTK PROTACs.