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Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious problem in current tumor therapy. A team of researchers at MD Anderson Cancer Center published a study in the Journal of Medicinal Chemistry on the DLK inhibitor IACS-52825, which showed that the drug significantly ameliorated chemotherapy-induced peripheral neuropathy in mice. Although a follow-up study terminated further development of the drug due to problems identified, the study provides new ideas for interventions in chemotherapy-induced neurotoxicity.

Chemotherapeutic agents inhibit tumor growth through their cytotoxic effects, but they also cause damage to normal cells, triggering different systemic side effects. Among them, peripheral neuropathy is a common long-term complication. Its pathogenesis is closely related to the activation of the DLK signaling pathway, a MAPK family protein kinase that is activated in response to neurological injury or stress, which triggers the downstream JNK signaling pathway and transcriptional response, leading to degeneration of nerve cells.

Pharmacokinetic Studies

The research team optimized a series of imidazole-based DLK inhibitors and found that one of the compounds, named IACS-52825 (22), has a high affinity to the nM level. This compound possesses good pharmacokinetic properties with insignificant in vivo inhibitory activity on specific channels and enzymes. It has good permeability and solubility in biologically relevant media, while exhibiting excellent in vitro microsomal and hepatocyte stability in different species. In addition, the compound has good bioavailability after oral administration and is able to cross the blood-brain barrier into brain tissue.

Table 1. Comparison of 19–22 In Vitro

Figure 1. X-ray structure of 22 (yellow) bound to DLK at 1.94 Å resolution. The CF3 group is arranged to make multipolar interactions with backbone carbonyl groups in the P-loop (blue ribbon). Distances shown are between fluorine atoms and carbonyl carbon atoms.

Experimental Cases

By conducting experiments in a mouse model, the researchers observed a dose-dependent effect of IACS-52825(22) on reversing chemotherapy-induced mechanical nociceptive hypersensitivity. In particular, at the highest dose, the chemotherapy-induced pain symptoms were almost completely reversed. Preclinical studies have shown a favorable safety profile for the compound, suggesting that DLK inhibition could be a potential treatment for already-developed CIPN.

To ensure the safety of the treatment, the research team conducted several pharmacokinetic and toxicology studies. In preclinical toxicity studies conducted in monkeys, optic nerve damage was observed. Considering the important role of DLK in maintaining visual axis function, this finding led to the termination of the program.

Preparation of DLK inhibitors

Despite the safety concerns of optic nerve damage with IACS-52825, this study still confirms the therapeutic potential of DLK inhibition for chemotherapy-induced neurotoxicity. This provides ideas for the development of new drugs targeting DLK. In the future, more precise dosing strategies need to be designed to avoid inhibiting normal DLK signaling and causing adverse visual effects. A balance between efficacy and safety needs to be sought to provide patients with more optimal treatment options.

Reference

1. Kang Le, Michael J. Soth, etal. Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy.  Discovery of IACS-52825, a Potent and Selective DLK Inhibitor for Treatment of Chemotherapy-Induced Peripheral Neuropathy. https://doi.org/10.1021/acs.jmedchem.3c00788.

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