Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1-Dependent Protein Aggregation for the Treatment of ALS

Abstract

Cyclohexane 1,3-diones were identified as a class of molecules exhibiting a protective effect against mutant SOD1 induced toxicity in PC-12 cells, but an optimized analogue had little or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional testing showed that these compounds were inactive in neurons and further analogue synthesis was carried out to identify compounds with neuronal activity. Starting from two racemic derivatives that were active in cortical neurons, two potent analogues (1b and 2b) were resolved, which were protective against mutant SOD1 induced toxicity in PC-12 cells. Both compounds were found to be active in cortical neurons and presented good ADME profiles in vitro. On the basis of these results, an ALS mouse trial with 1b was carried out, which showed slightly greater life extension than the FDA-approved ALS drug riluzole, thereby validating cyclohexane 1,3-diones as a novel therapeutic class for the treatment of ALS.

Modulating the Folding Landscape of Superoxide Dismutase 1 with Targeted Molecular Binders

“…Epitope‐specific antibodies and their antigen‐recognition regions as well as overexpressed heat shock proteins have shown some therapeutic benefit in ALS mouse models . Small molecules identified in cell‐based screens have also mitigated toxicity from SOD1 aggregation in preclinical studies, yet their biological targets remain unknown . We sought to combine the advantages of these approaches by exploring the small‐molecule‐targeted stabilization of key SOD1 epitopes so as to modify its folding energy landscape by stabilizing its folded structure while accelerating its folding.…”

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

“…Additionally, these compounds were found to be active in the cytotoxicity screen performed in SOD1 G93A-PC12 cells and displayed favorable PK profiles. Importantly, compound 15 exhibited a 90% increase in activity in primary cortical neurons [34]. Because of these favorable properties, this analogue was tested in SOD1 G93A transgenic mice that were treated daily by i.p.…”

“…administration with 30 mg/kg of CHD derivative compound 15 starting at 6 weeks (prior to symptom presentation). A 13% increase in lifespan was observed in treated animals as compared to controls [34]. …”

Modulating the Folding Landscape of Superoxide Dismutase 1 with Targeted Molecular Binders

“…[3,11,13] Small molecules identified in cell-based screens have also mitigated toxicity from SOD1 aggregation in preclinical studies, yet their biological targets remain unknown. [14] We sought to combine the advantages of these approaches by exploring the small-molecule-targeted stabilization of key SOD1 epitopes so as to modify its folding energy landscape by stabilizing its folded structure while accelerating its folding.…”