Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate–mediated regulation of cullin–RING ligase and sensitize cancer cells to MLN4924/pevonedistat
Xiaozhe Zhang, Shaodong Shi, Yang Su, Xiaoli Yang, Sining He, Xiuyan Yang, Jing Wu, Jian Zhang, Feng Rao
Abstract
-dependent sequestration of CRL by the deneddylase COP9 signalosome, thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbate the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic ef-fects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin's therapeutic effects.
Topics & Concepts
CullinSuraminInositolBiologyCell biologyChemistryUbiquitin ligaseCancer researchBiochemistryIn vitroReceptorUbiquitinGeneUbiquitin and proteasome pathwaysEndoplasmic Reticulum Stress and DiseasePeptidase Inhibition and Analysis