Current landscape and future perspectives of small-molecule therapeutics for Huntington's disease: From rational design to clinical translation.

Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene. Given their therapeutic potential, small-molecule strategies have gained significant traction, leading to the design of numerous lead candidates aimed at diverse pathological hallmarks of HD. These developmental efforts target various facets of the disease, including the inhibition and degradation of mutant huntingtin (mHTT) proteins, alleviation of motor dysfunction, and the provision of neuroprotective effects. For instance, gossypol acetate has been identified to induce the autophagic degradation of mHTT. Furthermore, these small molecules modulate critical signaling pathways within HD neurons, such as the store-operated calcium (SOC) channels, dopamine- and cAMP-regulated phosphoprotein 32 (DARPP-32), ataxia-telangiectasia mutated (ATM)/ataxia-telangiectasia and rad3-related (ATR)-p53 pathway, and the kynurenine (KYN) metabolic pathway. While currently explored small-molecule therapies have demonstrated preclinical efficacy, further clinical investigation is imperative to expand the chemical space of viable HD therapeutics. This review critically summarizes the design, synthesis, and structural motifs of small-molecule candidates, clinically used agents, and antioxidant natural products, providing a structural framework to guide the rational design and development of next-generation anti-HD compounds.