BLD-2736

**BLD-2736** is a novel, highly water-soluble small-molecule calpain inhibitor developed by Blade Therapeutics, targeting calpain-1, calpain-2, calpain-9, and cathepsin K with potency in the nanomolar range (IC50 nM). In preclinical studies using transgenic zebrafish models of spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease), BLD-2736 improved swimming ability, reduced insoluble ataxin-3 protein aggregates, decreased full-length and cleaved ataxin-3 levels, and enhanced autophagic flux via increased LC3II synthesis, even when treatment was delayed after aggregate formation. These neuroprotective effects support its potential for SCA3 and related polyglutamine neurodegenerative diseases, though it remains in preclinical development with no reported clinical trials[1][2][3][5].