Therapeutics: Src; tumor necrosis factor α (TNFα); interleukin-1β (IL-1β); tyrosine hydroxylase (TYH)

In vitro and mouse studies identified a phloroglucinol-based Src inhibitor that could help treat PD. Chemical synthesis and testing in a lipopolysaccharide (LPS)-stimulated mouse microglia of phloroglucinol analogs identified a compound that inhibited release of the neuroinflammation marker nitric oxide (NO) with an IC50 of 6.6 μM and decreased Src phosphorylation compared with no treatment. In an LPS-stimulated co-culture of mouse primary neurons and glia, the compound decreased levels of the inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) and increased levels of TYH, which catalyzes dopamine production. In three mouse models of PD, the compound decreased motor dysfunction, bradykinesia and midbrain levels of TNFα and IL-1β and increased the number of dopaminergic neurons in the substantia nigra and striatal levels of dopamine compared with no treatment. Next steps could include testing the safety of the compound in PD models.

AstraZeneca plc has the small molecule Src inhibitor AZD0424 in Phase I testing to treat solid tumors...