Suk Hyun, Scientific Analyst and Patent Agent (Volunteer) at Salk Institute Office of Technology Development, shared on LinkedIn:
“Science paper (29 Oct 26) introduces stimulated protein degradation (SPD), in which a small molecule activates a stress-responsive E3 ubiquitin ligase so it clears several of its own natural substrates at once, rather than recruiting a ligase to one disease protein, as PROTACs do.
Targeted protein degradation suits single-driver diseases, but its value in widespread protein dysregulation is unclear.
The authors chose CUL2-FEM1B, the reductive stress response ligase. It degrades proteins such as FNIP1 that block mitochondrial TOM import channels, which supports protein import and assembly of complex IV of the electron transport chain.
Brain-expressed X-linked (BEX) proteins inhibit the ligase by occupying its substrate pocket without being degraded, and the FEM1B R126A mutation displaces them.
The team screened about 120,000 compounds in paired fluorescence polarization assays (FEM1B with a BEX3 peptide versus an FNIP1 degron peptide) for molecules that remove the inhibitor but spare the substrate.
Hit BEX displacer 1 (BD1) blocked BEX3 binding with an IC50 near 2 µM and left FNIP1 binding intact up to 40 µM, while an 86 percent similar analog was inactive.
A crystal structure placed BD1 in the R126 pocket, contacting T120 and Y84, with no major conformational change, so displacement is competitive, not allosteric.
The cell-active analog BD2 displaced all detectable BEX proteins and lowered a mitochondrial FNIP1 reporter with a cellular IC50 of 1.1 µM, versus 7 µM in vitro, consistent with catalysis. BD2 also destabilized COA4, HK2 and SLC25A11 reporters, and all effects vanished when FEM1B was deleted or its pocket mutated. BD2 increased mitochondrial import, complex IV subunits and respiration without triggering reactive oxygen species.
In COX deficiency models, where loss of assembly factors cut respiratory capacity by 30 to 40 percent, BD2 restored it and prevented death of iPSC-derived neurons. In frataxin-depleted Friedreich’s ataxia models, BD2 matched optimal omaveloxolone, the approved KEAP1-targeting drug.
Limitations:
All data come from cultured cells (293T, C2C12, iPSC neurons), with no animal pharmacokinetics or efficacy. BD2 was used at up to 100 µM in some assays, so potency needs optimization. BD2 also occupies the R126 pocket used by C-end degron substrates and stabilized a CDK5R1 reporter at similar concentrations, so it is not a pure agonist.
Constitutive R126A activation depleted iPSCs, and the human R126Q variant causes a neurodevelopmental disorder, so safety of chronic activation is open. The toxicity advantage over omaveloxolone is a cell-level observation, and extension to other E3 ligases is proposed, not shown.”
Title: Stimulated protein degradation to promote mitochondrial function and neuronal survival
Authors: Srividya Chandrasekhar, Rachael McMinimy, Andrew G. Manford, Eddie Wehri, Christine L. Gee, Caitlyn Miller, Baris Bingol, John Kuriyan, Julia Schaletzky, Michael Rapé
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