SNIPER(TACC3)-1, a Novel Small Molecule Degrading the TACC3 Protein via the Ubiquitin-proteasome Pathway
Posted On 2019-05-26
Recently, the specific and nongenetic IAP-dependent protein eraser (SNIPER) is a novel approach to the treatment of various diseases, including cancer. SNIPER composes of two different ligands connected by a linker; one is a ligand for cellular inhibitor of apoptosis protein 1 (cIAP1) and the other a ligand for the target protein. Crucially, SNIPERs recruit inhibitor of the apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins. Especially, inhibitors of spindle-regulatory proteins have attracted considerable attention. Transforming acidic coiled-coil-3 (TACC3) is a spindle-regulatory protein.
In this study, N Ohoka, et al designed and synthesized the SNIPER(TACC3) to target the TACC3 protein for degradation. When human fibrosarcoma HT1080 cells are treated with graded concentrations of SNIPER(TACC3)-1 or SNIPER(TACC3)-2, the TACC3 level significantly decreases at 30 μM for 6 hour and at 10 μM for 24 hour. Besides, SNIPER(TACC3)s induce proteasomal degradation of the TACC3 protein. SNIPER(TACC3)s reduce TACC3 protein by a proteasome-dependent mechanism. SNIPER(TACC3) selectively induces cancer cell death expressing a large amount of the TACC3 protein. SNIPER(TACC3)s also decrease the cIAP1 level, suggesting that the SNIPER(TACC3)s simultaneously induces auto-ubiquitylation and proteasomal degradation of cIAP1. Researchers also show that cancer cells expressing a large amount of the TACC3 protein readily undergo cell death as the result of SNIPER(TACC3) treatment. SNIPER(TACC3) reduces the level of respective target proteins without reducing the other proteins, indicating the specificity of SNIPERs on the degradation of the target proteins.
In a word, SNIPER(TACC3)-1, a novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway, induces Cancer cell death.
Ohoka N, et al. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway. Cell Death Dis. 2014 Nov 6;5:e1513.