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Working model. HA-1141, on one hand, binds to UBA3 to inactivate NEDD8 E1, leading to neddylation inhibition of all cullins to cause accumulation of CRL substrates at early time points. On the other hand, HA-1141 triggers non-canonical ER stress, ISR and produces ROS to inactivate mTORC1 and inhibit protein synthesis, leading to reduction of CRL substrates and induction of autophagy at a later stage. See text for details.
