Yongying Jiang

Abstract Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18.

Introduction Ibrutinib (IBR) is an oral, small-molecule irreversible inhibitor of Bruton's tyrosine kinase (BTK) approved for treatment-naïve and relapsed/refractory (R/R) pts with CLL at a dose of 420 mg/d. IBR binds covalently to the C481 residue of BTK in a 1:1 stoichiometric ratio. In a phase 1 trial of IBR in pts with R/R B-cell malignancies, no MTD was identified, and ≥95% BTK occupancy was observed at doses ≥2.5 mg/kg/d and correlated with clinical response (Advani, JCO 2013).