On page 9, you clearly state that an ARE-directed PROTAC would likely degrade the entire sMAF family, including the essential transcription factors NRF1 and NRF3…. You rightly point out that this would cause a spectrum of off-target effects.
But then, the paper still seems to promote this as a promising therapeutic direction. This has me scratching my head.
Could you clarify how a therapeutic strategy that indiscriminately wipes out NRF1, a protein essential for basal cellular homeostasis, mitochondrial function, and is even lethal if knocked out in models, could ever be viable?
It feels like proposing to fix a broken window by burning down the whole house. The on-target toxicity would surely be unacceptable. Doesn’t this fundamental flaw completely undermine the clinical potential of this specific PROTAC approach, rather than just being a “hurdle to overcome”?
Thanks for any insight you can provide