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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.

SUBMITTER: Cetinkaya-Fisgin A

PROVIDER: S-EPMC8608988 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Cetinkaya-Fisgin Aysel A Zhu Jing J Luan Xinghua X Kim Jun-Soon JS Oh Byoungchol B Brayton Cory C Alt Jesse J Rais Rana R Slusher Barbara B Höke Ahmet A

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20210721 3

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 prope ...[more]

PMID: 34291431

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Project description:Background and purposeChemotherapy-induced peripheral neuropathy (CIPN) is perceived differently by patients and physicians, complicating its assessment. Current recommendations advocate combining clinical and patient-reported outcomes measures, but this approach can be challenging in patient care. This multicenter European study aims to bridge the gap between patients' perceptions and neurological impairments by aligning both perspectives to improve treatment decision-making.MethodsData were pooled from two prospective studies of subjects (n = 372) with established CIPN. Patient and physician views regarding CIPN were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Total Neuropathy Scale-clinical version (TNSc) items, and the disease-specific quality of life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20) from the European Organization for Research and Treatment of Cancer (EORTC). To identify inherent neurotoxic severity patterns, we employed hierarchical cluster analysis optimized with k-means clustering and internally validated by discriminant functional analysis.ResultsBoth NCI-CTCAE and TNSc demonstrated a significant difference in the distribution of severity grades in relation to QLQ-CIPN20 scores. However, a proportion of subjects with different neurotoxic severity grades exhibited overlapping QLQ-CIPN20 scores. We identified three distinct clusters classifying subjects as having severely impaired, intermediately impaired, and mildly impaired CIPN based on TNSc and QLQ-CIPN20 scores. No differences in demographics, cancer type distribution, or class of drug received were observed.ConclusionsOur results confirm the heterogeneity in CIPN perception between patients and physicians and identify three well-differentiated subgroups of patients delineated by degree of CIPN impairment based on scores derived from TNSc and QLQ-CIPN20. A more refined assessment of CIPN could potentially be achieved using the calculator tool derived from the cluster equations in this study. This tool, which facilitates individual patient classification, requires prospective validation.

Dataset Information

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

Publications

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

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