Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

Ambber Ward; Lilong Dong; Jonathan M. Harris; Kum Kum Khanna; Fares Al-Ejeh; David P. Fairlie; Adrian P. Wiegmans; Ligong Liu

doi:10.1016/j.bmcl.2017.05.039

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

Ambber Ward, Lilong Dong, Jonathan M. Harris, Kum Kum Khanna, Fares Al-Ejeh, David P. Fairlie, Adrian P. Wiegmans^*, Ligong Liu

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment.

Original language	English
Pages (from-to)	3096-3100
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2017.05.039
Publication status	Published - 2017
Externally published	Yes

Keywords

DNA repair
Homologous recombination
Inhibitor
RAD51
Triple-negative breast cancer

Access to Document

10.1016/j.bmcl.2017.05.039

Cite this

@article{105975d4537a49b99e996f56118b9588,

title = "Quinazolinone derivatives as inhibitors of homologous recombinase RAD51",

abstract = "RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment.",

keywords = "DNA repair, Homologous recombination, Inhibitor, RAD51, Triple-negative breast cancer",

author = "Ambber Ward and Lilong Dong and Harris, {Jonathan M.} and Khanna, {Kum Kum} and Fares Al-Ejeh and Fairlie, {David P.} and Wiegmans, {Adrian P.} and Ligong Liu",

note = "Publisher Copyright: {\textcopyright} 2017",

year = "2017",

doi = "10.1016/j.bmcl.2017.05.039",

language = "English",

volume = "27",

pages = "3096--3100",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "14",

}

TY - JOUR

T1 - Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

AU - Ward, Ambber

AU - Dong, Lilong

AU - Harris, Jonathan M.

AU - Khanna, Kum Kum

AU - Al-Ejeh, Fares

AU - Fairlie, David P.

AU - Wiegmans, Adrian P.

AU - Liu, Ligong

PY - 2017

Y1 - 2017

N2 - RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment.

AB - RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment.

KW - DNA repair

KW - Homologous recombination

KW - Inhibitor

KW - RAD51

KW - Triple-negative breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85019610567&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2017.05.039

DO - 10.1016/j.bmcl.2017.05.039

M3 - Article

C2 - 28545975

AN - SCOPUS:85019610567

SN - 0960-894X

VL - 27

SP - 3096

EP - 3100

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 14

ER -

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this