Farnesyl Transferase (FTase) is a heterodimeric enzyme containing α and β subunit in mammalian cells. FTase is one of the three enzymes in the prenyltransferase group. The activity of FTase requires both Zn²⁺ and Mg²⁺. FTase can bind to farnesyl pyrophosphate (FPP) and peptide substrate independently. The β subunit of FTase binds to FPP with a very high affinity without covalent bond formation. FTase catalyzes farnesylation, resulting in prenylation of the cysteine in the C-terminal CAAX motif of p21-Ras. FTase regulates the activation of Ras protein and consequently affects intracellular signal transduction, cell growth and proliferation.

FTase’s targets include members of the Ras superfamily of small GTP-binding proteins critical to cell cycle progression. FTase selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. For this reason, several FTase inhibitors are undergoing testing as anti-cancer agents. FTase inhibitors block the farnesylation of Ras in a dose-dependent manner in cancer cells growing in tissue culture. Meanwhile, FTase inhibitors have shown efficacy as anti-parasitic agents. What’s more, FTase inhibitors also play an important role in development of progeria.

Tipifarnib (IND 58359), a nonpeptidomimetic, is a potent and orally active FTase inhibitor. Specifically, Tipifarnib blocks the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive. Tipifarnib inhibits farnesylation of lamin B and K-RasB peptide substrates. Therefore, Tipifarnib inhibits tumor growth in vitro and in vivo. Tipifarnib shows potent efficacy in the research of HRAS mutant head and neck cancer, peripheral T-cell lymphoma, myelodysplastic syndromes, chronic myelomonocytic leukemia, breast cancer, and multiple myeloma.

In summary, Tipifarnib is a potent and orally active inhibitor of FTase. Tipifarnib exhibits antineoplastic activity in vitro and in vivo.

References:

Wang J, et, al. Medchemcomm. 2017 Feb 16;8(5):841-854.