URMC-099 is an orally bioavailable, brain penetrant MLK inhibitor (IC50: 19/42/14/150 nM, for MLK1/MLK2/MLK3/DLK), and also inhibits LRRK2 activity (IC50: 11 nM).

LCK:333 nM, ROCK2:111 nM, SRC:4330 nM, MLK2:42nM, Syk:731 nM, FLT3:4 nM, TRKA:85 nM, JNK1:3280 nM, TNF-α:460 nM, MEKK2:661 nM, SGK:67 nM, CDK1:1125 nM, FLT1:39 nM, DLK:150 nM, Abl-1 (T315I):3 nM, ROCK1:1030 nM, CDK2:1180 nM, p38α:12050 nM, IKKα:591 nM, Aurora A:108 nM, c-Met:177 nM, SGK1:201 nM, Aurora C:290 nM, MLK3:14nM, ZAP70:5050 nM, ABL1:6.8 nM, MLK1:19nM, LRRK2:11 nM, ERK2:6290 nM, IGF-1R:307 nM, IKKβ:257 nM, Aurora B:123 nM, TRKB:217 nM, CYP3A4:16.2 μM, AMPK:1512 nM

URMC-099, administered intraperitoneally (i.p.) at a dosage of 10 mg/kg, demonstrates the ability to reduce the production of inflammatory cytokines within the body, protect neuronal structures, and alter the morphology and ultrastructural response of microglia to exposure to HIV-1 Tat. In mice, URMC-099 exhibits favorable pharmacokinetics and enhanced Central Nervous System (CNS) penetration. Additionally, URMC-099 significantly reduces the infiltration of neutrophils into the peritoneum of wild-type mice in response to fMLP.

URMC-099 reduces chemotaxis in wild-type neutrophils induced by fMLP in vitro. Moreover, URMC-099 inhibits the release of TNFα in microglia triggered by lipopolysaccharides, as well as the release of cytokines in human monocytes stimulated by HIV-1 Tat. Additionally, URMC-099 prevents the destruction and phagocytosis of cultured neuronal axons by microglia.

HDAC IC50 Profiling: The in vitro inhibitory activity of compounds against seven human HDAC isoforms (1, 2, 4 C2A, 5 C2A, 6, 8, and 11) are performed with a fluorescent based assay according to the company's standard operating procedure. The IC50 values are determined using 10 different concentrations with 3-fold serial dilution starting at 10 μM. TSA and vorinostat are used as reference compounds.