Introducing Borsantrazole: A Trifunctional Boron‐Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered a highly complex, heterogeneous, fatal disease with a high unmet medical need that affects multiple pathophysiological pathways and has no known singular cause. Oxidative stress, however, is implicated as a central player in the progression of ALS and other neurodegenerative diseases. To date, only two FDA-approved drugs, Edaravone, an antioxidant, and Riluzole, an antiglutamatergic, have been widely used clinically, albeit with modest effects on the clinical course of ALS disease progression. Additionally, preclinical studies of both drugs in ALS mouse models have not shown any significant survival benefit, although some abatement in disease progression is observed and translated from preclinical animal models to clinical human studies. METHODS: Using a trifunctional boron-based drug design strategy, we have synthesized a pyrazole small molecule called Borsantrazole (BSZ) and evaluated BSZ in cell-based experiments, acute and chronic toxicity models, and the SOD1-G37R ALS mouse model. We have also evaluated untargeted global proteomic and phosphoproteomic changes induced by BSZ. RESULTS: Borsantrazole (a small molecule that can selectively target oxidative stress) with favorable CNS drug like properties (low ER values of 0.9 and 1.0 at 1 and 10 µm, respectively, suggesting lower Pgp efflux liability and the LogD at pH 7.4 was within the range of 1.2 to 3.1, suggesting BSZ is lipophilic at pH 7.4.) shows no signs of treatment associated toxicity (acute or chronic (120 days)), significantly increases survival (whole animals, 15.1 days (p = 0.0326); males, 16.5 days; females, 13.7 days), rescued weight loss (27.1% control, 18.3% BSZ, p < 0.0001), delays symptom onset (whole animals, 24.9 days (p = 0.0011); males, 23.3 days; females, 26.4 days), delays disease onset (whole animals, 25.5 days (p = 0.0001); males, 21.1 days; females, 29.8 days) and affects global proteomic changes in the SOD1-G37R mouse model of ALS. In total, 51 proteins were found to be significantly differentially expressed (p < 0.05), including Ca3, Gan, Cplx2, Lrp4, Sqstm1, and 29 phosphorylation sites were differentially expressed and considered statistically significant, including T317 and T72 for neurofilaments light and heavy chain, respectively. CONCLUSIONS: Herein, we report that BSZ has demonstrated a favorable safety profile and compelling proof-of-concept efficacy in a ALS mouse model and has the potential to become a disease-modifying ALS therapeutic following further clinical development. Within a broader perspective of treatments for neurodegenerative diseases, BSZ offers a new paradigm for trifunctional small molecule targeting of oxidative stress that can mitigate neuronal deterioration and serve as a potential treatment.