GGTI 2133 (trifluoroacetate salt)

GGTI 2133 is a peptidomimetic inhibitor of geranylgeranyl transferase type I (GGTase I; IC₅₀ = 38 nM). It is 140-fold selective for GGTase I over farnesyltransferase (IC₅₀ = 5,400 nM). In vitro, it inhibits geranylgeranylation of RAP1A (IC₅₀ = 10 μM) without inhibiting farnesylation of H-Ras (IC₅₀ = >30 μM). It also inhibits cell growth and decreases migration and invasion of oral squamous cell carcinoma (OSSC) cells to 75, 45, and 27% of control values, respectively. GGTI 2133 (5 mg/kg per day, i.p.) prevents ovalbumin-induced eosinophil infiltration into airways in a mouse model of allergic bronchial asthma but does not prevent an increase in chemokines. It also blocks naloxone-induced contraction of ileum isolated from rats with morphine withdrawal syndrome and dose-dependently decreases withdrawal severity in vivo (ED₅₀ = 0.076 mg/kg).

GGTI-2133 has been used

• To understand the role of geranylgeranyl transferase in the regulation of CXC chemokine production and neutrophil recruitment in the lung.
• To study the importance of geranylgeranylation in cell adhesion.
• To measure ligand-induced ADP-ribosylation factor 6 (Arf6) activation in breast cancer cells.

GGTase I mediates prenylation to induce the oncogenic functions of the Ras and Rho proteins. Thus, GGTase I inhibitors can be utilized as effective anticancer drugs. They are also useful in treating inflammation, atherosclerosis, multiple sclerosis and other diseases.

[1] ANIL VASUDEVAN. Potent, Highly Selective, and Non-Thiol Inhibitors of Protein Geranylgeranyltransferase-I[J]. Journal of Medicinal Chemistry, 1999, 42 8: 1333-1340. DOI: 10.1021/jm9900873
[2] MASAKAZU HAMADA. Involvement of RhoA and RalB in geranylgeranyltransferase I inhibitor-mediated inhibition of proliferation and migration of human oral squamous cell carcinoma cells.[J]. Cancer Chemotherapy and Pharmacology, 2011, 68 3: 559-569. DOI: 10.1007/s00280-010-1520-9
[3] Y CHIBA  M M  S Sato. GGTI-2133, an inhibitor of geranylgeranyltransferase, inhibits infiltration of inflammatory cells into airways in mouse experimental asthma.[J]. International Journal of Immunopathology and Pharmacology, 2009, 22 4: 929-935. DOI: 10.1177/039463200902200408
[4] ASHISH K. REHNI  Thakur G S. Pharmacological modulation of geranylgeranyltransferase and farnesyltransferase attenuates opioid withdrawal in vivo and in vitro[J]. Neuropharmacology, 2013, 71: Pages 19-26. DOI: 10.1016/j.neuropharm.2013.01.022