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DRB is a nucleoside analog that inhibits several carboxyl-terminal domain (CTD) kinases including casein kinase II (IC50 = 4-10 µM)1, cyclin-dependent kinase 7 (CDK7) (IC50 = ~20 µM)2,3, CDK8 (IC50 = ~20 µM)3, and CDK9 (IC50 = 3 µM).4 Through inhibition of certain CTD kinases, DRB inhibits an elongation step during RNA polymerase II transcription5,6, which can trigger p53-dependent apoptosis of human colon adenocarcinoma cells without inducing genotoxic stress to healthy cells.7 DRB can also inhibit HIV transcription (IC50 = ~4 µM) by targeting elongation enhanced by the HIV-encoded transactivator Tat.8
1
Zandomeni, R.O. Kinetics of inhibition by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole on calf thymus casein kinase II. Biochem J262469-473(1989).
2
Yankulov, K., Yamashita, K., Roy, R., et al. The transcriptional elongation inhibitor 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole inhibits transcription factor IIH-associated protein kinase. J Biol Chem270(41)23922-23925(1995).
3
Rickert, P., Corden, J.L., and Lees, E. Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases. Oncogene181093-1102(1999).
4
Schang, L.M. Cyclin-dependent kinases as cellular targets for antiviral drugs. J Antimicrob Chemother50779-792(2002).
5
Zandomeni, R., Zandomeni, M.C., Shugar, D., et al. Casein kinase type II is involved in the inhibition by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole of specific RNA polymerase II transcription. J Biol Chem261(7)3414-3419(1986).
6
Yamaguchi, Y., Wada, T., and Handa, H. Interplay between positive and negative elongation factors: drawing a new view of DRB. Genes Cells39-15(1998).
7
te Poele, R.H., Okorokov, A.L., and Joel, S.P. RNA synthesis block by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) triggers p53-dependent apoptosis in human colon carcinoma cells. Oncogene185765-5772(1999).
8
Marciniak, R.A., and Sharp, P.A. HIV-1 tat protein promotes formation of more-processive elongation complexes. EMBO J10(13)4189-4196(1991).
Zandomeni, R.O. Kinetics of inhibition by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole on calf thymus casein kinase II. Biochem J262469-473(1989).
Rickert, P., Corden, J.L., and Lees, E. Cyclin C/CDK8 and cyclin H/CDK7/p36 are biochemically distinct CTD kinases. Oncogene181093-1102(1999).
Yamaguchi, Y., Wada, T., and Handa, H. Interplay between positive and negative elongation factors: drawing a new view of DRB. Genes Cells39-15(1998).
Marciniak, R.A., and Sharp, P.A. HIV-1 tat protein promotes formation of more-processive elongation complexes. EMBO J10(13)4189-4196(1991).
Schang, L.M. Cyclin-dependent kinases as cellular targets for antiviral drugs. J Antimicrob Chemother50779-792(2002).
te Poele, R.H., Okorokov, A.L., and Joel, S.P. RNA synthesis block by 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) triggers p53-dependent apoptosis in human colon carcinoma cells. Oncogene185765-5772(1999).
Nam, K.A., Kim, S., Heo, Y.H., et al. Resveratrol analog, 3,5,2',4'-tetramethoxy-trans-stilbene, potentiates the inhibition of cell growth and induces apoptosis in human cancer cells. Arch Pharm Res24(5)441-445(2001).
Yankulov, K., Yamashita, K., Roy, R., et al. The transcriptional elongation inhibitor 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole inhibits transcription factor IIH-associated protein kinase. J Biol Chem270(41)23922-23925(1995).