{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:55:08Z","timestamp":1790603708834,"version":"4.1.0"},"reference-count":162,"publisher":"Wiley","issue":"54","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2010approved 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a trifunctional boron\u2010based drug design strategy, we have synthesized a pyrazole small molecule called Borsantrazole (BSZ) and evaluated BSZ in cell\u2010based experiments, acute and chronic toxicity models, and the SOD1\u2010G37R ALS mouse model. We have also evaluated untargeted global proteomic and phosphoproteomic changes induced by BSZ.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u00a0\u00b5\n                      <jats:sc>m<\/jats:sc>\n                      , 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 (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0326); males, 16.5 days; females, 13.7 days), rescued weight loss (27.1% control, 18.3% BSZ,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001), delays symptom onset (whole animals, 24.9 days (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0011); males, 23.3 days; females, 26.4 days), delays disease onset (whole animals, 25.5 days (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0001); males, 21.1 days; females, 29.8 days) and affects global proteomic changes in the SOD1\u2010G37R mouse model of ALS. In total, 51 proteins were found to be significantly differentially expressed (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Herein, we report that BSZ has demonstrated a favorable safety profile and compelling\n                      <jats:italic>proof\u2010of\u2010concept<\/jats:italic>\n                      efficacy in a ALS mouse model and has the potential to become a disease\u2010modifying 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/advs.76432","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T03:31:58Z","timestamp":1785123118000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Introducing Borsantrazole: A Trifunctional Boron\u2010Based Pyrazole That Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5716-3992","authenticated-orcid":false,"given":"Nitesh","family":"Sanghai","sequence":"first","affiliation":[{"name":"College of Pharmacy University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda","family":"Kelley","sequence":"additional","affiliation":[{"name":"Central Animal Care University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Lao","sequence":"additional","affiliation":[{"name":"Manitoba Centre for Proteomics and Systems Biology University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Immanuel Reyes","family":"Madlangsakay","sequence":"additional","affiliation":[{"name":"Manitoba Centre for Proteomics and Systems Biology University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanta","family":"Paul","sequence":"additional","affiliation":[{"name":"Manitoba Centre for Proteomics and Systems Biology University of Manitoba  Winnipeg Manitoba Canada"},{"name":"Department of Internal Medicine University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Alejandra","family":"Llanes\u2010Cuesta","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 P.","family":"Zahedi","sequence":"additional","affiliation":[{"name":"Manitoba Centre for Proteomics and Systems Biology University of Manitoba  Winnipeg Manitoba Canada"},{"name":"Department of Internal Medicine University of Manitoba  Winnipeg Manitoba Canada"},{"name":"Department of Biochemistry and Medical Genetics University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiming","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Cell Science University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-8685","authenticated-orcid":false,"given":"Geoffrey K.","family":"Tranmer","sequence":"additional","affiliation":[{"name":"College of Pharmacy University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"issue":"1","key":"e_1_2_13_2_1","first-page":"1","article-title":"Amyotrophic Lateral Sclerosis","volume":"3","author":"Hardiman O.","year":"2017","journal-title":"Nature reviews Disease primers"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1603471"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12408"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/362059a0"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.47.6_Suppl_4.233S"},{"issue":"1","key":"e_1_2_13_7_1","first-page":"25","article-title":"Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis","volume":"43","author":"Cruz M. 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