4-CPPC is a reversible, selective small molecule inhibitor of the pro-inflammatory protein macrophage migration inhibitor-2 (MIF-2), with Ki values of 431±37 and 33±0.7µM for MIF-1 and MIF-2, respectively[1]. 4-CPPC inhibits MIF-1 by specifically binding to its C-terminal region and inducing conformational changes[1].
In vitro, pre-treatment with 10μM 4-CPPC for 30min, followed by overnight incubation with 1μg/mL MIF-2, attenuated Low-Density Lipoprotein (LDL) uptake in PBMC-derived macrophages[2]. Treatment of primary astrocytes with 100μM 4-CPPC for 24h attenuated MIF-2 (1μg/mL)-induced activation of the COX-2/PGE2 (Cyclooxygenase-2/Prostaglandin E2) pathway[3].
In vivo, intraperitoneal administration of 4-CPPC (5mg/kg, every other day over 4.5 weeks) markedly reduced aortic root lesion size, along with lesional macrophages and circulating cytokines/chemokines (e.g., IL-1α, IL-6, IL-15, and IFN-γ) in Apolipoprotein E knockout (Apoe–/–) mice[2]. In a rat spinal cord injury (SCI) model, intrathecal injection of 8μL 100mM 4-CPPC at the lesion site increased BBB (Basso, Beattie, and Bresnahan) scores within 21 days, significantly improving hindlimb motor recovery[3].
References:
[1] Pantouris G, Bucala R, Lolis EJ. Structural Plasticity in the C-Terminal Region of Macrophage Migration Inhibitory Factor-2 Is Associated with an Induced Fit Mechanism for a Selective Inhibitor. Biochemistry. 2018;57(26):3599-3605.
[2] El Bounkari O, Zan C, Yang B, et al. An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. Nat Commun. 2025;16(1):2297.
[3] Ji H, Zhang Y, Chen C, et al. D-dopachrome tautomerase activates COX2/PGE2 pathway of astrocytes to mediate inflammation following spinal cord injury. J Neuroinflammation. 2021;18(1):130.
4-CPPC是一种可逆的，选择性的促炎蛋白巨噬细胞迁移抑制因子-2（MIF-2）的小分子抑制剂，对MIF-1和MIF-2的Ki值分别为431±37和33±0.7µM。4-CPPC通过特异性结合MIF-1的C端区域并诱导构象变化，从而发挥抑制作用[1]。
体外实验中，10μM 4-CPPC预处理30分钟后，与1μg/mL MIF-2共同孵育过夜，可抑制PBMC来源巨噬细胞中的低密度脂蛋白（LDL）摄取[2]。用100μM 4-CPPC处理原代星形胶质细胞24小时，可减弱1μg/mL MIT-2诱导的胞内环氧合酶-2/前列腺素E2（COX-2/PGE2）通路的激活[3]。
体内实验中，在载脂蛋白E敲除（Apoe⁻/⁻）小鼠中，以5mg/kg剂量腹腔注射4-CPPC（每隔一天一次，持续4.5周）可显著降低主动脉根部斑块面积，并伴随病灶巨噬细胞及循环细胞因子/趋化因子的减少（如IL-1α、IL-6、IL-15和IFN-γ）[2]。在大鼠脊髓损伤模型中，于病变部位鞘内注射8μL 100mM 4-CPPC，可在21天内提高BBB运动评分，显著改善后肢运动功能恢复[3]。