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

Abstract

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.

Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis

“…If EQ-6 is identified to exert neuroprotective effects in animal models of CNS diseases as well, it might be worth developing and utilizing EQ-6 as a promising pharmacological approach to prevent neurodegeneration, given that EQ-6 is likely to accumulate in neural tissue and lacks significant genotoxicity and carcinogenicity. 51 Other strategies that can also reduce SF3B2 levels include anti-sense oligos, which have been shown to be effective in several neurodegenerative studies including spinal muscular atrophy and amyloid neuropathy. 53,54 A major challenge in developing therapies for CNS axonal protection is targeting the appropriate cell types while reducing complications due to off-target side effects.…”

“…Our previous studies found that ethoxyquin (EQ) and its novel analog, EQ‐6 (6‐(5‐amino)‐ethoxy‐2,2,4‐trimethyl‐1,2‐dihydroquinoline hydrochloride), prevent axonal degeneration induced in rat dorsal root ganglion (DRG) neurons treated with cisplatin or paclitaxel and mouse models of chemotherapy‐induced peripheral neuropathy (CIPN) 7,51,52 . EQ is an FDA‐approved food preservative, and it is added in animal feed 51 .…”

“…Our previous studies found that ethoxyquin (EQ) and its novel analog, EQ‐6 (6‐(5‐amino)‐ethoxy‐2,2,4‐trimethyl‐1,2‐dihydroquinoline hydrochloride), prevent axonal degeneration induced in rat dorsal root ganglion (DRG) neurons treated with cisplatin or paclitaxel and mouse models of chemotherapy‐induced peripheral neuropathy (CIPN) 7,51,52 . EQ is an FDA‐approved food preservative, and it is added in animal feed 51 . Through subsequent experiments, we showed that EQ interacts with heat shock protein 90 (Hsp90) and negatively modulates its chaperone function, resulting in diminished cellular level of SF3B2 protein 7,52 .…”

“…It remains unclear whether EQ or EQ‐6 can provide CNS protection following inflammatory injury. If EQ‐6 is identified to exert neuroprotective effects in animal models of CNS diseases as well, it might be worth developing and utilizing EQ‐6 as a promising pharmacological approach to prevent neurodegeneration, given that EQ‐6 is likely to accumulate in neural tissue and lacks significant genotoxicity and carcinogenicity 51 . Other strategies that can also reduce SF3B2 levels include anti‐sense oligos, which have been shown to be effective in several neurodegenerative studies including spinal muscular atrophy and amyloid neuropathy 53,54 …”

Prevention and therapy of chemotherapy-induced peripheral neuropathy: a review of recent findings

“…EQ-6 (6-(5-amino)-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride), a novel analog of the known antioxidant ethoxyquin, prevents axonal degeneration in primary DRG neurons and epidermal nerve fiber loss in vitro and in a murine model of paclitaxel-induced CIPN, respectively. Cetinkaya-Fisgin et al demonstrated that this axonal protection is associated with preserved levels of nicotinamide adenine dinucleotide, a key metabolite in the programmed pathway of axonal degeneration [115].…”