URMC-099, as a 7‐azaindole‐based MLK3 inhibitor with IC50 of 14 nM, could specifically affect specific Aβ species engaged in disease pathobiology[1].
In vitro, the average half maximal inhibitory concentrations (IC50) of URMC-099 in seven GBM cell lines was 4.57 μM. In vitro, treatment with ≥ 5 μM URMC-099 for 48 h in 7 GBM cell lines reduced cell viability[2]. In vitro experiment it shown that treatment with 100 or 300 nM URMC-099 in neuronal cell prevented neuronal death and maintained healthy neurites up to 48 h after NGF withdrawal in a dose-dependent manner[3]. In vitro, URMC-099 treatment (100 nm) reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells[4].
In vivo, URMC-099 treatment in C57BL/6 mice (10 mg/kg, i.v.) reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure[4]. In vivo efficacy test it shown that 10 mg/kg URMC‐099 (i.p.) prophylaxis prevents the induction of VCAM‐1 in the SLM of 6‐month‐old CVN‐AD (APPSwDI/mNos2−/− AD) mice following surgery[5]. In vivo, prophylactic URMC-099 (10 mg/kg, i.p.) treatment in mice is sufficient to prevent surgery-induced microgliosis and cognitive impairment without affecting fracture healing[6].
References:
[1] Goodfellow VS, Loweth CJ, Ravula SB, Wiemann T, Nguyen T, Xu Y, Todd DE, Sheppard D, Pollack S, Polesskaya O, Marker DF, Dewhurst S, Gelbard HA. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48.
[2] Zhao HF, et al. Synergism between the phosphatidylinositol 3-kinase p110β isoform inhibitor AZD6482 and the mixed lineage kinase 3 inhibitor URMC-099 on the blockade of glioblastoma cell motility and focal adhesion formation. Cancer Cell Int. 2021 Jan 6;21(1):24.
[3] Bellizzi MJ, et al. The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis. eNeuro. 2018 Dec 3;5(6):ENEURO.0245-18.2018.
[4] Marker DF, 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 Jun 12;33(24):9998-10010.
[5] Miller-Rhodes P, et al. URMC-099 prophylaxis prevents hippocampal vascular vulnerability and synaptic damage in an orthopedic model of delirium superimposed on dementia. FASEB J. 2022 Jun;36(6):e22343.
[6] Miller-Rhodes P, et al. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193.
URMC-099作为一种基于7-氮杂吲哚的MLK3抑制剂，其IC50为14 nM，可特异性影响参与疾病病理生物学的特定aβ物种[1]。
在体外，在7个GBM细胞系中，≥5 μM URMC-099作用48小时降低了细胞活力。URMC-099在7个GBM细胞系中的平均半最大抑制浓度（IC50）为4.57 μM[2]。体外实验表明，在神经元细胞中用100或300 nM URMC-099处理可以以剂量依赖的方式防止神经元死亡，并在NGF停药后48小时内保持健康的轴突[3]。在体外，URMC-099治疗（100nm）减少了暴露于HIV-1Tat的小胶质细胞产生的炎症细胞因子，并阻止了这些细胞对培养的神经元轴突的破坏和吞噬[4]。
在体内，URMC-099在C57BL/6小鼠中的治疗（10 mg/kg，静脉注射）减少了炎症细胞因子的产生，保护了神经元结构，并改变了小胶质细胞对HIV-1Tat暴露的形态学和超微结构反应[4]。体内疗效测试表明，10 mg/kg URMC‐099（i.p.）预防可防止手术后6个月大的CVN‐AD（APPSwDI/mNos2−/-AD）小鼠SLM中VCAM‐1的诱导[5]。体内预防性URMC-099（10 mg/kg，i.p.）治疗小鼠足以在不影响骨折愈合的情况下预防手术诱导的小胶质细胞增生和认知障碍[6]。