Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors

Evgeny Kiselev, Azhar Ravji, Jayakanth Kankanala, Jiashu Xie, Zhengqiang Wang, Yves Pommier

Research output: Contribution to journalArticle

Abstract

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5′-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. TDP2 is a logical target for the development of therapeutics to complement existing treatments based on inhibition of TOP2. There is, however, no TDP2 inhibitor in clinical development at present. Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. Recently we reported new subtypes derived within the deazaflavin family with improved membrane permeability properties. In this work we characterize two representative analogues from two new deazaflavin subtypes based on their biochemical TDP2 inhibitory potency and drug-likeness. We demonstrate that the ZW-1288 derivative represents a promising direction for the development of deazaflavins as therapeutic agents. ZW-1288 exhibits potent inhibitory activity at low nanomolar concentrations against recombinant and cellular human TDP2 with profile similar to that of the parent analog SV-5-153 based on high resistance against murine TDP2 and human TDP2 mutated at residue L313H. While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors.

Original languageEnglish (US)
Article number102747
JournalDNA Repair
Volume85
DOIs
StatePublished - Jan 2020

Fingerprint

Phosphodiesterase Inhibitors
Etoposide
DNA Repair Enzymes
Lead compounds
Camptothecin
Mitoxantrone
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Topoisomerase I Inhibitors
tyrosyl-DNA phosphodiesterase
DNA Cleavage
Cytotoxicity
DNA
Prostate
Chickens
Permeability
Lymphoma
Leukemia
Derivatives
Membranes

Keywords

  • Deazaflavin
  • Etoposide
  • Inhibitor
  • Mitoxantrone
  • Topoisomerase
  • Tyrosyl-DNA phosphodiesterase

PubMed: MeSH publication types

  • Journal Article

Cite this

Kiselev, E., Ravji, A., Kankanala, J., Xie, J., Wang, Z., & Pommier, Y. (2020). Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. DNA Repair, 85, [102747]. https://doi.org/10.1016/j.dnarep.2019.102747

Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. / Kiselev, Evgeny; Ravji, Azhar; Kankanala, Jayakanth; Xie, Jiashu; Wang, Zhengqiang; Pommier, Yves.

In: DNA Repair, Vol. 85, 102747, 01.2020.

Research output: Contribution to journalArticle

Kiselev, Evgeny ; Ravji, Azhar ; Kankanala, Jayakanth ; Xie, Jiashu ; Wang, Zhengqiang ; Pommier, Yves. / Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. In: DNA Repair. 2020 ; Vol. 85.
@article{a5dd95837bde47618e4f38c721e22b1d,
title = "Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors",
abstract = "Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5′-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. TDP2 is a logical target for the development of therapeutics to complement existing treatments based on inhibition of TOP2. There is, however, no TDP2 inhibitor in clinical development at present. Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. Recently we reported new subtypes derived within the deazaflavin family with improved membrane permeability properties. In this work we characterize two representative analogues from two new deazaflavin subtypes based on their biochemical TDP2 inhibitory potency and drug-likeness. We demonstrate that the ZW-1288 derivative represents a promising direction for the development of deazaflavins as therapeutic agents. ZW-1288 exhibits potent inhibitory activity at low nanomolar concentrations against recombinant and cellular human TDP2 with profile similar to that of the parent analog SV-5-153 based on high resistance against murine TDP2 and human TDP2 mutated at residue L313H. While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors.",
keywords = "Deazaflavin, Etoposide, Inhibitor, Mitoxantrone, Topoisomerase, Tyrosyl-DNA phosphodiesterase",
author = "Evgeny Kiselev and Azhar Ravji and Jayakanth Kankanala and Jiashu Xie and Zhengqiang Wang and Yves Pommier",
year = "2020",
month = "1",
doi = "10.1016/j.dnarep.2019.102747",
language = "English (US)",
volume = "85",
journal = "DNA Repair",
issn = "1568-7864",
publisher = "Elsevier",

}

TY - JOUR

T1 - Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors

AU - Kiselev, Evgeny

AU - Ravji, Azhar

AU - Kankanala, Jayakanth

AU - Xie, Jiashu

AU - Wang, Zhengqiang

AU - Pommier, Yves

PY - 2020/1

Y1 - 2020/1

N2 - Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5′-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. TDP2 is a logical target for the development of therapeutics to complement existing treatments based on inhibition of TOP2. There is, however, no TDP2 inhibitor in clinical development at present. Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. Recently we reported new subtypes derived within the deazaflavin family with improved membrane permeability properties. In this work we characterize two representative analogues from two new deazaflavin subtypes based on their biochemical TDP2 inhibitory potency and drug-likeness. We demonstrate that the ZW-1288 derivative represents a promising direction for the development of deazaflavins as therapeutic agents. ZW-1288 exhibits potent inhibitory activity at low nanomolar concentrations against recombinant and cellular human TDP2 with profile similar to that of the parent analog SV-5-153 based on high resistance against murine TDP2 and human TDP2 mutated at residue L313H. While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors.

AB - Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5′-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. TDP2 is a logical target for the development of therapeutics to complement existing treatments based on inhibition of TOP2. There is, however, no TDP2 inhibitor in clinical development at present. Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. Recently we reported new subtypes derived within the deazaflavin family with improved membrane permeability properties. In this work we characterize two representative analogues from two new deazaflavin subtypes based on their biochemical TDP2 inhibitory potency and drug-likeness. We demonstrate that the ZW-1288 derivative represents a promising direction for the development of deazaflavins as therapeutic agents. ZW-1288 exhibits potent inhibitory activity at low nanomolar concentrations against recombinant and cellular human TDP2 with profile similar to that of the parent analog SV-5-153 based on high resistance against murine TDP2 and human TDP2 mutated at residue L313H. While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors.

KW - Deazaflavin

KW - Etoposide

KW - Inhibitor

KW - Mitoxantrone

KW - Topoisomerase

KW - Tyrosyl-DNA phosphodiesterase

UR - http://www.scopus.com/inward/record.url?scp=85075292119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075292119&partnerID=8YFLogxK

U2 - 10.1016/j.dnarep.2019.102747

DO - 10.1016/j.dnarep.2019.102747

M3 - Article

C2 - 31775111

AN - SCOPUS:85075292119

VL - 85

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

M1 - 102747

ER -