PIK5-12d is a highly potent, selective, first-in-class PIKfyve PROTAC degrader, potently degrades PIKfyve protein with DC50 value of 1.48 nM and Dmax value of 97.7% in prostate cancer VCaP cells.
PIK5-12d (100 nM) causes fast degradation of PIKfyve protein with a t1/2 value of 1.5 h in VCaP cells, also effectively reduces PIKfyve in other prostate cancer PC3, LNCaP, and 22RV1 cells.
PIK5-12d is a highly specific PIKfyve degrader with only 3 proteins significantly downregulated including PIKfyve, which accounts for the off-target rate at 2 out of 7573 detectable proteins.
PIK5-12d is selective for PIKfyve over other lipid kinases.
PIK5-12d mediated-PIKfyve degradation is VHL and proteasome-dependent.
PIK5-12d induces massive cytoplasmic vacuolization and blocks autophagy in prostate cancer cells.
PIK5-12d inhibits VCaP cell proliferation with an IC50 of 522.3 nM, exerts prolonged suppression of PIKfyve downstream signaling.
PIK5-12d (10 mg/kg) almost completely depleted PIKfyve protein in LTL-331R human prostate cancer patient-derived xenograft (PDX) model, significantly suppressed tumor proliferation in vivo.