Halofuginone hydrobromide (RU-19110 (hydrobromide))

Halofuginone hydrobromide (RU-19110 hydrobromide) is a less-toxic form of Febrifugine, which is isolated from the plant Dichroa febrifuga[1]. Halofuginone inhibits prolyl-tRNA synthetase in an ATP-dependent manner with a Ki of 18.3 nM[2]. Halofuginone attenuates osteoarthritis (OA) by inhibition of TGF-β activity[3].

Halofuginone competitively inhibits prolyl-tRNA synthetase by occupying both the prolineand tRNA-binding pockets of prolyl-tRNA synthetase[1]. The IC50s of Halofuginone (1, 10, 100, 1000, 10000 nM; 48 hours) are 114.6 and 58.9 nM in KYSE70 and A549 cells, respectively. The IC50s of Halofuginone (1, 10, 100, 1000 nM; 24 hours) for NRF2 protein are 22.3 and 37.2 nM in KYSE70 and A549 cells, respectively. The IC50 of Halofuginone for global protein synthesis is 22.6 and 45.7 nM in KYSE70 and A549 cells, respectively[1].|| Cell Viability Assay[1]||Cell Line:|KYSE70 cells from human oesophageal cancer harbouring a mutation in the NRF2 gene and A549 cells harbouring theKEAP1 gene mutation|Concentration:|1, 10, 100, 1000, 10000 nM|Incubation Time:|48 hours|Result:|The IC50s were 114.6 and 58.9 nM in KYSE70 and A549 cells, respectively.|| Western Blot Analysis[1]||Cell Line:|KYSE70 cells from human oesophageal cancer harbouring a mutation in the NRF2 gene and A549 cells harbouring theKEAP1 gene mutation.|Concentration:|1, 10, 100, 1000 nM|Incubation Time:|24 hours|Result:|The IC50s for NRF2 protein were 22.3 and 37.2 nM in KYSE70 and A549 cells, respectively.

Halofuginone attenuates progression of OA in anterior cruciate ligament transection (ACLT) mice. The optimal dose (1 mg/kg body weight) is identified using multiple concentrations of HF (0.2, 0.5, 1 or 2.5 mg/kg) injected every other day for 1 month post surgery. Lower concentration (0.2 or 0.5 mg/kg) has minimal effects on subchondral bone and higher concentration (2.5 mg/kg) induces proteoglycan loss in articular cartilage[3]. Halofuginone (0.25-mg/kg, intraperitoneally) decreases NRF2 protein levels in tumors. While the tumor volumes do not change substantially between treatments with the vehicle, Halofuginone(0.25 mg/kg, intraperitoneally injected, every day) or cisplatin alone, combined treatment with Halofuginone and Cisplatin significantly suppresses the tumor volume compared to treatment with Halofuginone or cisplatin alone[1].

[1]. Tsuchida K, et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic Biol Med. 2017 Feb;103:236-247. [2]. Keller TL, et al. Halofuginone and other Febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol. 2012 Feb 12;8(3):311-7. [3]. Cui Z, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone. Ann Rheum Dis. 2016 Sep;75(9):1714-21.