URMC-099

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Background

URMC-099 is an orally bioavailable and brain penetrant inhibitor of MLK3 with IC50 value of 14 nM [1].
Mixed Lineage Kinase 3 (MLK3) is a member of the serine/threonine kinase family that regulate MAPK8/JNK signaling cascade and also activates ERK and p38. MLK3 activation can result in the stimulation of cell motility and migration [1] [2].
URMC-099 is a novel and orally bioavailable MLK3 inhibitor. In murine BV-2 microglial cells, URMC-099 inhibited LPS-induced TNFαrelease. In primary human monocytes, URMC-099 inhibited HIV-1 Tat-induced release of cytokines [1]. In neutrophils, URMC-099 reduced chemotaxis induced by fMLP and inhibited fMLP-stimulated F-actin formation [2].
In Tat-injected brains of mice, URMC-099 inhibited up-regulation of phospho-JNK. In HIV-1 Associated Neurocognitive Disorders (HAND) preclinical models, URMC-099 inhibited multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). URMC-099 reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure [1] [3]. In wild-type C57Bl/6 mice, URMC-099 inhibited fMLP-induced accumulation of neutrophils in the peritoneum [2]. In infected humanized NOD/SCID/IL2Rγc-/-mice, URMC-099 administered with nanoATV dose-dependently reduced HIV-1p24 viral load and reverse transcriptase activity, as well as the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues [4].

[1]. Goodfellow VS, Loweth CJ, Ravula SB, et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem, 2013, 56(20): 8032-8048.
[2]. Polesskaya O, Wong C, Lebron L, et al. MLK3 regulates fMLP-stimulated neutrophil motility. Mol Immunol, 2014, 58(2): 214-222.
[3]. Marker DF, Tremblay MÈ, Puccini JM, et al. The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders. J Neurosci, 2013, 33(24): 9998-10010.
[4]. Zhang G, Guo D, Dash PK, et al. The Mixed Lineage Kinase-3 Inhibitor URMC-099 Improves Therapeutic Outcomes for Long-Acting Antiretroviral Therapy. Nanomedicine, 2015. pii: S1549-9634(15)00187-2.