Furamidine

Furamidine (DB75) is abisbenzamidine derivative and an antiparasite agent. Furamidine is a potent, reversible and competitive tyrosyl-DNA phosphodiesterase 1 (TDP-1) inhibitor. Inhibition of TDP-1 by Furamidine is effective both with single- and double-stranded DNA substrates but is slightly stronger with the duplex DNA. Furamidine is also a selective and cell-permeable protein arginine methyltransferase 1 (PRMT1) inhibitor with an IC50 of 9.4 μM. Furamidine is selective for PRMT1 over PRMT5, PRMT6, and PRMT4 (CARM1) (IC50s of 166 µM, 283 µM, and >400 µM, respectively)[1][2][3].

Research Areas >> Cancer

Research Areas >> Infection

Signaling Pathways >> Epigenetics >> Histone Methyltransferase

Research Areas >> Inflammation/Immunology

Tyrosyl-DNA phosphodiesterase 1 (TDP-1)[1] Parasite[2] IC50: 9.4 μM (Protein arginine methyltransferase 1 (PRMT1)); 166 µM (PRMT5), 283 µM (PRMT6) and >400 µM (PRMT4)[2]

Furamidine (compound 1; 20 μM; 72 hours; leukemia cell lines) inhibits cell growth for most of the leukemia cell lines except HEL cells which have JAK2V617F mutations[2]. Furamidine (compound 1; 20 μM; 15 hours; 293T cells) treatment significantly reduces the expression level of the methylated GFP-ALY protein in 293T cells[2]. Furamidine binds duplex DNA in the DNA minor groove selectively at AT rich sites [(A/T)4]. Furamidine can also intercalate between GC base pairs of duplex DNA. Furamidine could therefore interfere with DNA processing enzymes such as TDP-1[1]. Cell Viability Assay[2] Cell Line: Meg-01, K562, HL-60, NB4, MOLM13, HEL, CMK, CMY, CMS and CHRF cells Concentration: 20 μM Incubation Time: 72 hours Result: Inhibited cell growth for most of the leukemia cell lines except HEL cells which have JAK2V617F mutations. Western Blot Analysis[2] Cell Line: 293T cells Concentration: 20 μM Incubation Time: 15 hours Result: The expression level of the methylated GFP-ALY protein is significantly reduced.

Furamidine (1 mg/kg; intraperitoneal injection; 3 times a week and repeated every 4 weeks; for 34 weeks; female NZB/NZW mice) and Irinotecan combined treatment suppresses proteinuria and prolongs survival of lupus-prone NZB/NZW mice. The combination treatment does not change the levels of anti-dsDNA antibodies[3]. Animal Model: Female NZB/NZW mice (6-week-old) with Irinotecan (1 mg/kg)[3] Dosage: 1 mg/kg Administration: Intraperitoneal injection; 3 times a week and repeated every 4 weeks; for 34 weeks Result: Suppressed proteinuria and prolongs survival of lupus-prone NZB/NZW mice combined with Irinotecan.

[1]. Antony S, et al. Novel high-throughput electrochemiluminescent assay for identification of human tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors and characterization of furamidine (NSC 305831) as an inhibitor of Tdp1. Nucleic Acids Res. 2007;35(13):4474-84.

[2]. Yan L, et al. Diamidine compounds for selective inhibition of protein arginine methyltransferase 1. J Med Chem. 2014 Mar 27;57(6):2611-22.

[3]. Keil A, et al. The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis. Arthritis Rheumatol. 2015 Jul;67(7):1858-67.