Lonafarnib

Lonafarnib is a farnesyltransferase inhibitor that blocks the post-translational lipid modification of oncogenic Ras isoforms H-Ras, N-Ras, and K-Ras (IC₅₀s = 1.9, 2.8, and 5.2 nM, respectively) as well as Rheb (IC₅₀ = 10-100 nM).^1,2 It inhibits H-Ras signaling in whole cells (IC₅₀ = 10 nM) and blocks the transformed growth properties of fibroblasts (IC₅₀ = 75 nM) and human tumor cell lines (IC₅₀ = 400 nM) expressing activated K-Ras proteins. In the nude mouse, lonafarnib demonstrates potent dose-dependent oral activity in an array of human tumor xenograft models including tumors originating from colon, lung, pancreas, prostate, and urinary bladder.¹ Combination treatments with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine) or MAPK or Akt pathway inhibitors can enhance the in vivo efficacy of lonafarib.^1,3

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1. Liu, M., Bryant, M.S., Chen, J., et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and Wap-ras transgenic mice. Cancer Res. 58(21), 4947-4956 (1998).

2. Basso, A.D., Mirza, A., Liu, G., et al. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. The Journal of Biological Chemisty 280(35), 31101-31108 (2005).

3. Niessner, H., Beck, D., Sinnberg, T., et al. The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. J. Invest. Dermatol. 131(2), 468-479 (2011).

Cuddy, L.K., Alia, A.O., Salvo, M.A., et al. Farnesyltransferase inhibitor LNK-754 attenuates axonal dystrophy and reduces amyloid pathology in mice. Mol. Neurodegener. 17(1), 54 (2022).