GGTI 2133 is a highly selective peptidomimetic inhibitor of geranylgeranyl transferase type I (PGGTase-I), with IC₅₀ values of 38nM and 5.4μM for PGGTase-I and farnesyl transferase (FTase), respectively, indicating 140-fold selectivity[1].
In vitro, GGTI 2133 inhibited Rap1A processing in NIH3T3 cells with an IC₅₀ of 10μM, but had no effect on H-Ras processing, with an IC₅₀ exceeding 30μM[1]. Incubation with 10μM GGTI 2133 for 28h reduced CD4⁺T cell expansion but not CD8⁺T cell expansion, and inhibited ERK1/2 phosphorylation in T cells stimulated with CD3/CD28 beads[2].
In vivo, in male BALB/c mice with allergic bronchial asthma, once-daily intraperitoneal administration of GGTI 2133 (5mg/kg/day) for 10 days alleviated eosinophilic airway inflammation, primarily by inhibiting eosinophil infiltration into the airways[3].
References:
[1] Vasudevan A, Qian Y, Vogt A, et al. Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I. J Med Chem. 1999;42(8):1333-1340.
[2] Hechinger AK, Maas K, Dürr C, et al. Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells. Haematologica. 2013;98(1):31-40.
[3] Chiba Y, Sato S, Misawa M. GGTI-2133, an inhibitor of geranylgeranyltransferase, inhibits infiltration of inflammatory cells into airways in mouse experimental asthma. Int J Immunopathol Pharmacol. 2009;22(4):929-935.
GGTI 2133是一种高度选择性的肽模拟型GG转移酶I（PGGTase-I）抑制剂，其对PGGTase-I和法尼基转移酶（FTase）的IC₅₀值分别为38nM和5.4μM，对PGGTase-I表现出约140倍的选择性[1]。
体外实验中，GGTI 2133在NIH3T3细胞中抑制Rap1A的加工，其IC₅₀值为10μM，但对H-Ras的加工无影响，其IC₅₀值超过30μM[1]。用10μM GGTI 2133孵育28h可减少CD4⁺T细胞的扩增，但对CD8⁺T细胞的扩增无明显影响，同时可抑制CD3/CD28球粒刺激的T细胞中ERK1/2的磷酸化水平[2]。
体内实验中，在患有过敏性支气管哮喘的雄性BALB/c小鼠中，每日一次腹腔注射GGTI 2133（5mg/kg/day），连续10天，可改善嗜酸性气道炎症，主要表现为抑制嗜酸性粒细胞向气道的浸润[3]。