Photoswitchable Molecular Glues Enable Optical Control of Transcription Factor Degradation

Abstract

Immunomodulatory drugs (IMiDs), which include thalidomide and its derivatives, have emerged as the standard of care against multiple myeloma. They function as molecular glues that bind to the E3 ligase cereblon (CRBN) and induce protein interactions with neosubstrates, including the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). The subsequent ubiquitylation and degradation of these transcription factors underlies the antiproliferative activity of IMiDs. Here, we introduce photoswitchable immunomodulatory drugs (PHOIMiDs) that can be used to degrade Ikaros and Aiolos in a light-dependent fashion. Our lead compound shows minimal activity in the dark and becomes an active degrader upon irradiation with violet light. It shows high selectivity over other transcription factors, regardless of its state, and could therefore be used to control the levels of Ikaros and Aiolos with high spatiotemporal precision.

Photoswitchable Auxin-Inducible Degron System for Conditional Protein Degradation with Spatiotemporal Resolution

“…Moreover, washing the auxin ligand to achieve reversibility is not a rational choice when continuous data acquisition is necessary with a stable medium to monitor a real-time dynamic biological process. Our group and others have achieved spatiotemporal control over various biological systems by integrating molecular photoswitches into the structure of biologically active small molecules, − including proteolysis-targeting chimeras (PROTACs), − which are deeply relevant to the present work.…”

“…We treated HAP1 cells stably expressing OsTIR1 F74G and a mAID-fused enhanced green fluorescent protein (GFP) with a nuclear localization signal (mAID–EGFP–NLS) reporter ,,, with dimethyl sulfoxide (DMSO) (control), 1 , or 2 for 4 h at 37 °C in dark and light to test the gluing ability of the ligands. A 365 nm light source with 0.2 mW cm –2 intensity and a 405 nm light source with 0.8 mW cm –2 intensity were used to irradiate 1 and 2 , respectively, to maintain the Z -rich PSS without affecting cell viability.…”