Unraveling the Engagement of Kinases to CRBN Through a Shared Structural Motif to Optimize PROTACs Efficacy

PROteolysis TArgeting Chimeras (PROTACs) offer a therapeutic modality for protein target engagement, exploiting the ubiquitin–proteasome system to achieve precise degradation of a protein of interest. Recent advancements in understanding the structural biology of the CRL4A E3 ligase complex, particularly its recruitment of neo-substrates through the G-loop motif, have provided valuable insights into the optimization of PROTAC efficacy. This perspective delves into the molecular determinants governing PROTAC selectivity and degradation efficiency, with a specific focus on kinases showing distinct G-loop conformations. By employing computational approaches to predict ternary complexes, along with the identification of binding patterns, it is possible to address limitations posed by structural data scarcity, thereby enhancing rational design strategies.