From undruggable to degradable: development of anthraquinone-based PROTACs against MITF for skin-lightening applications

Microphthalmia-associated transcription factor (MITF) is a master regulator of melanogenesis but remains undruggable. We designed anthraquinone-2-carboxylic acid-based PROTACs; EF4 exhibited the most potent degradation in A375B16-F10 cells with minimal cytotoxicity. CETSA and proteasome inhibition assays confirmed target engagement, and molecular docking revealed a stable MITF–EF4–CRBN ternary complex. ADMET profiling showed favorable properties (MW 564.6, logP 2.62, bioavailability 0.55). Compared to E6, EF4 had fewer drug-likeness violations, better skin permeability (log Kp = −7.76 cm/s), and superior synthetic accessibility. These findings highlight EF4 as a promising lead for skin-targeted MITF degraders.