Discovery of Potent, Selective DNMT1 PROTAC Degraders: Simultaneous Blockade of Catalytic and Non-Catalytic Functions for Liver Fibrosis Therapy

Abstract Liver fibrosis is a progressive pathological condition driven by chronic hepatic injury and currently lacks effective therapies. DNA methyltransferase 1 (DNMT1) promotes fibrogenesis through both catalytic and non-catalytic mechanisms. To simultaneously target these dual functions, we designed and synthesized a series of DNMT1-targeting PROTAC degraders based on DC-517. Our optimization campaign culminated in compound B7, which emerged as the most potent agent, mediating ubiquitin-proteasomal degradation of DNMT1. In vitro, B7 reduced global DNA methylation and altered readouts associated with reported catalytic and non-catalytic functions of DNMT1, concomitant with suppression of profibrotic responses. In vivo, B7 administration reduced DNMT1 expression and attenuated liver fibrosis, as evidenced by decreased collagen deposition and improved hepatic function. Overall, these findings indicate that DNMT1 degradation could be a viable approach for liver fibrosis and provide a proof of concept for applying PROTAC technology to fibrotic diseases.