Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents

Abstract

Protein-protein interaction inhibitor of the sodium NaV1.7 channel has analgesic effects in preclinical models of pain.

Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces and prevents pain chronification in a mouse model of oxaliplatin-induced neuropathic pain

“…1 C ). Treatment with 194 had no effect on animals treated with vehicle instead of oxaliplatin, suggesting no effect of 194 on basal mechanical sensation, which is in line with our previous observations ( Cai et al, 2021 ).…”

“…Since multiple anti-neoplastic agents are employed in the clinic, it is important to establish that new analgesic candidates are effective in treating neuropathy induced by agents from multiple therapeutic classes. Considering the need for therapies for CIPN, and the importance of cross species validation, we asked whether 194 could reverse mechanical allodynia associated with CIPN in a similar fashion to what we observed previously in paclitaxel treated rats ( Cai et al, 2021 ). Male mice were injected with oxaliplatin, between days 0–4 and 10–14, followed by assessment of paw withdrawal thresholds ( Fig.…”

“…Subsequent in vitro characterization of the top scoring compounds revealed a benzoylated 2-(4-piperidinyl)-1,3-benzimidazole analog capable of interfering with CRMP2 SUMOylation, which we refer to as compound 194 ( Fig. 1 A ) ( Cai et al, 2021 , Kingwell, 2021 ). A recent report from our group outlines the promising characteristics of 194 , which shows excellent specificity for inhibiting NaV1.7 currents in cultured DRG neurons ( Cai et al, 2021 ).…”

“…1 A ) ( Cai et al, 2021 , Kingwell, 2021 ). A recent report from our group outlines the promising characteristics of 194 , which shows excellent specificity for inhibiting NaV1.7 currents in cultured DRG neurons ( Cai et al, 2021 ). Treatment with 194 reduced membrane localization of NaV1.7 in a clathrin-dependent manner and reduced presynaptic NaV1.7 in the spinal cord.…”

“…Treatment with 194 reduced membrane localization of NaV1.7 in a clathrin-dependent manner and reduced presynaptic NaV1.7 in the spinal cord. Furthermore, treatment with compound 194 reversed mechanical allodynia following spared nerve injury (SNI) and after treatment with paclitaxel in male rats ( Cai et al, 2021 ). Since vesicular trafficking and membrane localization of NaV1.7 are increased in CIPN, it is possible that treatment with 194 could normalize this dysregulated trafficking to restore normal levels of nociception.…”