A Dual-Sensor-Based Screening System for In Vitro Selection of TDP1 Inhibitors

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  • Ann-Katrine Jakobsen
  • Josephine Geertsen Keller-Socin
  • Maria Gonzales, Departament de Química Orgánica I and Lascaray Research Center, Facultad de Farmacia, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Paseo de la Universidad 7 Vitoria 01006, Denmark
  • Endika Martín-Encinas, University of the Basque Country (UPV/EHU), University of the Basque Country, Spain
  • Francisco Palacios, University of the Basque Country (UPV/EHU), University of the Basque Country, Spain
  • Concepción Alonso, University of the Basque Country (UPV/EHU), University of the Basque Country, Spain
  • Birgitta R. Knudsen
  • Magnus Stougaard
DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.
Original languageEnglish
Article number4832
Publication statusPublished - 15 Jul 2021

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