UK-5099 is a mitochondrial pyruvate carrier (MPC) inhibitor with an IC50 value of 50nM for inhibiting pyruvate-dependent O2 consumption[1]. UK-5099 is an α-cyanocinnamate derivative that blocks pyruvate entry into mitochondria, impairs mitochondrial oxidative phosphorylation and triggers aerobic glycolysis[2]. UK-5099 can increase glutamate oxidation and prevent excitotoxic neuronal death[3].
In vitro, UK-5099 (25, 50µM) treatment of bone marrow-derived macrophages for 30min dose-dependently reduced the formation of the adaptor protein apoptosis-associated speck-like protein containing CARD (ASC)[4]. UK-5099 (40, 80µM) treatment of microglia significantly reduced the nuclear signal intensity of NF-κB and NF-IL6 in cells[5]. UK-5099 (10-150µM) treatment of 832/13 cells dose-dependently inhibited glucose-stimulated insulin secretion in cells[6].
In vivo, UK-5099 (3mg/kg) was intraperitoneally injected into mice bearing non-small cell lung cancer xenografts and synergized with syrosingopine to inhibit tumor growth[7].
References:
[1] Halestrap A P. The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors[J]. Biochemical Journal, 1975, 148(1): 85-96.
[2] Zeng Q, Si H, Lv K, et al. Determination and pharmacokinetics study of UK-5099 in mouse plasma by LC–MS/MS[J]. BMC Veterinary Research, 2022, 18(1): 145.
[3] Quansah E, Peelaerts W, Langston J W, et al. Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration[J]. Molecular Neurodegeneration, 2018, 13: 1-12.
[4] Ran L, Chen M, Ye J, et al. UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long‐Established Target Mitochondrial Pyruvate Carrier[J]. Advanced Science, 2024, 11(33): 2307224.
[5] Guimarães N C, Alves D S, Vilela W R, et al. Mitochondrial pyruvate carrier as a key regulator of fever and neuroinflammation[J]. Brain, Behavior, and Immunity, 2021, 92: 90-101.
[6] Patterson J N, Cousteils K, Lou J W, et al. Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion[J]. Journal of Biological Chemistry, 2014, 289(19): 13335-13346.
[7] Li Y, Song Y, Shi Z, et al. Syrosingopine and UK5099 synergistically suppress non-small cell lung cancer by activating the integrated stress response[J]. Cell Death & Disease, 2024, 15(6): 431.
UK-5099是一种线粒体丙酮酸载体（MPC）抑制剂，抑制丙酮酸依赖性O2消耗的IC50值为50nM[1]。UK-5099是一种α-氰基肉桂酸酯衍生物，能够阻断丙酮酸进入线粒体，削弱线粒体氧化磷酸化并触发有氧糖酵解[2]。UK-5099能够增加谷氨酸氧化，防止兴奋性毒性神经元死亡[3]。
在体外，UK-5099（25, 50µM）处理骨髓来源的巨噬细胞30min，剂量依赖性地剂量依赖性地减少了衔接蛋白凋亡相关斑点样蛋白含有CARD（ASC）的形成[4]。UK-5099（40, 80µM）处理小胶质细胞，显著降低了细胞中NF-κB和NF-IL6的核信号强度[5]。UK-5099（10-150µM）处理832/13细胞，剂量依赖性地抑制了细胞中葡萄糖刺激的胰岛素分泌[6]。
在体内，UK-5099（3mg/kg）通过腹腔注射治疗非小细胞肺癌异种移植小鼠，与昔洛舍平协同抑制了肿瘤生长[7]。