Development of EQ-6, a Novel Analogue of Ethoxyquin to Prevent Chemotherapy-Induced Peripheral Neuropathy

Aysel Cetinkaya-Fisgin, Jing Zhu, Xinghua Luan, Jun Soon Kim, Byoungchol Oh, Cory Brayton, Jesse Alt, Rana Rais, Barbara Slusher, Ahmet Höke

Research output: Contribution to journalArticlepeer-review


Chemotherapy-induced peripheral neuropathy (CIPN) is a common and often dose-limiting side effect of many cancer drugs. Because the onset of neuronal injury is known, it is an ideal clinical target to develop neuroprotective strategies. Several years ago, we had identified ethoxyquin as a potent neuroprotective drug against CIPN through a phenotypic drug screening and demonstrated a novel mechanism of action, inhibition of chaperone domain of heat shock protein 90. To improve its drug-like properties we synthesized a novel analogue of ethoxyquin and named it EQ-6 (6-(5-amino)-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride). Here we show that EQ-6 prevents axon degeneration in primary dorsal root ganglion neurons in vitro, and this axon protection is associated with preserved levels of nicotinamide adenine dinucleotide, a key metabolite in programmed axon degeneration pathway. We also found that EQ-6 prevents loss of epidermal nerve fibers in a mouse model of CIPN induced by paclitaxel and that doses of EQ-6 that provide neuroprotection are associated with reduced tissue levels of SF3B2, a potential biomarker of target engagement. Furthermore, we show that EQ-6 is safe in vitro and in mice with daily administration for a month. We found that oral bioavailability is about 10%, partly due to rapid metabolism in liver, but EQ-6 appears to be concentrated in neural tissues. Given these findings, we propose EQ-6 as a first-in-class drug to prevent CIPN.

Original languageEnglish (US)
Pages (from-to)2061-2072
Number of pages12
Issue number3
StatePublished - Jul 2021


  • Chemotherapy-induced peripheral neuropathy
  • Ethoxyquin
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)


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