Mechanistic description
USP14 Inhibition to Accelerate Proteasomal Degradation of Synaptic Substrates
Evidence for (5)
USP14 inhibition enhances proteasome activity and reduces polyglutamine aggregation
USP14 knockdown improves synaptic function in aging Drosophila models
Proteasome subunits show reduced activity in AD hippocampus with accumulation of ubiquitinated proteins
IU1 derivatives penetrate blood-brain barrier and reduce protein aggregates in mouse models
DUBs are considered more druggable than transcription factors with defined active sites
Evidence against (6)
VLX1570 DUB inhibitor reached Phase 1/2 and was terminated due to toxicity (cardiac/vascular)
USP14 knockout mice develop sensorineural defects indicating essential functions
IU1 inhibits otulin and CYLD at relevant concentrations - poor selectivity
b-AP15/PR-157 acts on proteasome 19S subunit PSMD4, not USP14
USP14 performs quality control editing of ubiquitin chains - complete inhibition eliminates checkpoint
Proteasome 'bounce-back' response triggers compensatory downregulation after pharmacologic activation
Bayesian persona consensus
scidex.consensus.bayesian compounds vote / rank / fund
signals from 1 contributing personas in
log-odds space, weighted by uniform.
Prior 50%.