Optimization of Allosteric Regulators of the NaV1.7 Sodium Channel for Chemotherapy-induced Peripheral Neuropathy (CIPN)

National Center For Advancing Translational Sciences

Investigators

Abstract

Long-term use of opioids to treat chronic pain caused by chemotherapy-induced peripheral neuropathy (CIPN) can result in tolerance and addiction amongst other health problems. There is a distinct need for safe, effective, and non-addictive drugs with novel mechanisms of action to help improve quality of life for those that suffer from neuropathic pain. NCATS' collaboration with Regulonix focuses on a groundbreaking strategy to target the NaV1.7 channel, a well-validated pain target. Collapsin response mediator protein 2 (CRMP2) SUMOylation regulates NaV1.7 trafficking to the cell surface. Modulating this process selectively reduces surface NaV1.7 expression, thereby attenuating pain signaling. This approach offers a first-in-class, groundbreaking mechanism for pain modulation by precisely controlling NaV1.7 activity via CRMP2 SUMOylation. This collaboration addresses the HEAL Initiative’s goal to develop a novel, non-opioid target for chronic pain. Towards this end, the NCATS team established a robust screening platform that integrates multiplexed assays using rDRG neurons and human iPSC-derived nociceptors to evaluate efficacy and cytotoxicity. Concurrently, we conducted hERG testing, in vitro ADME profiling, and in vivo PK studies to guide medicinal chemistry. The team performed extensive optimization efforts utilizing several different strategies to identify several preclinical leads. Throughout optimization, the team generated over >550 novel compounds. Optimized leads demonstrate potent activity in multiple functional assays, favorable CNS/PNS distribution, metabolic stability, and no hERG liability. Critically, in vivo studies using the spared nerve ligation (SNL) pain model revealed significant reductions in both tactile and cold allodynia after oral administration, evidence of robust analgesic efficacy at therapeutically relevant exposures. Building on these successes, ongoing studies in additional pain models are underway to identify a candidate with IND-enabling potential. As a backup strategy, we performed multiple rounds of virtual screening using machine learning/QSAR and pharmacophore-based docking, identifying over 100 virtual-screen hits and analogs. Several novel hybrid analogs were synthesized based on these hits. We are now evaluating these lead molecules in in vivo pain models to select the preclinical candidate. The team filed a patent (WO/2025/129167), and the technology is under licensing negotiations with external partners for further clinical development. Several manuscripts are currently in preparation as well.