鉴定首创（first-in-class）的选择性ARID1B降解剂

ARID1B, a core component of the SWI/SNF chromatin remodeling complex, has long been considered undruggable due to the absence of known binders and lack of ligandable pockets. Striking dependency on ARID1B is observed across multiple cancer indications harboring ARID1A mutations, including endometrial, ovarian, and gastric cancers. This highlights the synthetic lethal relationship between the two paralogs and establishes ARID1B as a high value target for precision oncology. We report the discovery and optimization of first in class selective ARID1B degraders for the treatment of ARID1A mutant cancers. Using our platform and structure based design, we first identified several selective ARID1B binder series, which were then used to develop VHL and CRBN based molecules that induce robust ARID1B degradation via the ubiquitin-proteasome system. These compounds exhibit on mechanism activity, high selectivity, and downstream transcriptional modulation. This work establishes ARID1B degradation as a promising therapeutic strategy and provides a blueprint for targeting previously intractable chromatin remodelers.