URMC-099 is an orally absorbable, brain-penetrating inhibitor of mixed-lineage kinases (MLKs), exhibiting 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 demonstrated the ability to reduce inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevent the destruction and phagocytosis of cultured neuronal axons by these cells. In rodent models of HIV-associated neurocognitive disorders, URMC-099 shows anti-inflammatory and neuroprotective effects.