Disrupting BRD4-BD1–p62 Engagement Restores Protective Autophagy [RNA-seq]

Here, we identify SKLB-39b, a BRD4-BD1-selective inhibitor that restores protective autophagy and attenuates pulmonary fibrosis. SKLB-39b exhibits over 100-fold selectivity for BRD4-BD1 relative to BRD4-BD2 and nearly 10-fold greater affinity for BRD4-BD1 than for BRD2/3-BD1.

Mechanistically, we identify a BRD4-BD1-p62 interaction that links BET bromodomain function to autophagy regulation. By engaging Leu92 and Ile146 through a hydrophobic binding mode, SKLB-39b disrupts this interaction, restores ULK1-dependent autophagy, and provides a structural framework for BD1-selective inhibitor design. SKLB-39b outperformed JQ-1 in suppressing fibroblast activation, epithelial-mesenchymal transition, and collagen deposition in experimental fibrosis while showing favorable pharmacokinetic exposure and no overt toxicity in the mouse studies performed.