URMC-099 is an orally bioavailable, brain-penetrant inhibitor of mixed-lineage kinases (MLKs) with IC50 values of 19, 42, 14, and 150 nM for MLK1, MLK2, MLK3, and the related MLK family member DLK, respectively. It also inhibits LRRK2 activity with an IC50 value of 11 nM. In vitro, URMC-099 has been shown to reduce inflammatory cytokine production by HIV-1 Tat-exposed microglia and to prevent destruction and phagocytosis of cultured neuronal axons by these cells. In rodent models of HIV-associated neurocognitive disorders, URMC-099 demonstrates anti-inflammatory and neuroprotective effects.
