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.