Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

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

doi:10.1016/j.bmcl.2017.05.039

Cited by 19 publications

(12 citation statements)

References 20 publications

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“…The first RAD51 inhibitors developed by our group, RI-1 (41)a nd RI-2 (42), represent ac lass of compounds that block RAD51-ssDNA nucleoprotein filament formation and subsequent strand ex- change. [18,20,42,43] Halenaquinone (46), 2h, 2i,a nd 10 e belong to a second class of compounds purported to target strand exchange while permitting the bindingo fR AD51 to ssDNA. [18,20,42,43] Halenaquinone (46), 2h, 2i,a nd 10 e belong to a second class of compounds purported to target strand exchange while permitting the bindingo fR AD51 to ssDNA.…”

Section: Discussionmentioning

confidence: 99%

“…[14,17] Other compounds in this class include DIDS (43), IBR 120 (44), B02 (45), and ar ecently developed analogue of 45 with greaters ingle-agent potency against tumor cell lines. [18,20,42,43] Halenaquinone (46), 2h, 2i,a nd 10 e belong to a second class of compounds purported to target strand exchange while permitting the bindingo fR AD51 to ssDNA. [21,44] These findings represent am ajor advance in the development of RAD51-targeting smallm olecules.…”

Section: Discussionmentioning

confidence: 99%

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Optimization of Drug Candidates That Inhibit the D‐Loop Activity of RAD51

et al. 2019

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RAD51 is the central protein in homologous recombination (HR) repair, where it first binds ssDNA and then catalyzes strand invasion via a D‐loop intermediate. Additionally, RAD51 plays a role in faithful DNA replication by protecting stalled replication forks; this requires RAD51 to bind DNA but may not require the strand invasion activity of RAD51. We previously described a small‐molecule inhibitor of RAD51 named RI(dl)‐2 (RAD51 inhibitor of D‐loop formation #2, hereafter called 2 h), which inhibits D‐loop activity while sparing ssDNA binding. However, 2 h is limited in its ability to inhibit HR in vivo, preventing only about 50 % of total HR events in cells. We sought to improve upon this by performing a structure–activity relationship (SAR) campaign for more potent analogues of 2 h. Most compounds were prepared from 1‐(2‐aminophenyl)pyrroles by forming the quinoxaline moiety either by condensation with aldehydes, then dehydrogenation of the resulting 4,5‐dihydro intermediates, or by condensation with N,N′‐carbonyldiimidazole, chlorination, and installation of the 4‐substituent through Suzuki–Miyaura coupling. Many analogues exhibited enhanced activity against human RAD51, but in several of these compounds the increased inhibition was due to the introduction of dsDNA intercalation activity. We developed a sensitive assay to measure dsDNA intercalation, and identified two analogues of 2 h that promote complete HR inhibition in cells while exerting minimal intercalation activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Optimization of Drug Candidates That Inhibit the D‐Loop Activity of RAD51

et al. 2019

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“…Furthermore, inhibitors 17 notably hamper TNBC cell sensitivity to DNA damage. This would be potentially targeted therapy for cancer treatment [65].…”

Section: Biological Activities Of Quinazolinone and Quinazoline Derivmentioning

confidence: 99%

Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application

Mishra

2020

Quinazolinone and Quinazoline Derivatives

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Drug discovery and optimization comprise one of the most significant targets in medicinal chemistry. Quinazoline and quinazolinone derivatives and nitrogencontaining heterocycles have received significant attention due to their widely and distinct biopharmaceutical activities. Quinazolines and quinazolinones are considered as noteworthy chemical for the synthesis of diverse physiological significance and pharmacological utilized molecules. Quinazolines are building blocks for about 150 naturally occurring alkaloids with a broad range of biological activity. The various substituted quinazolines and quinazolinones displayed important, for example, sedative hypnotics, antibacterial, anti-inflammatory, analgesic, antipsychotic, antifungal, antimalarial, anticonvulsant, anti-Parkinsonism, cancer, and other activities. This chapter aims to highlight the latest evidence of quinazolinone and quinazoline derivatives as a privileged scaffold in medicinal chemistry.

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“…Having established an enhanced homologous recombination repair phenotype in chemoresistant cell lines, we wondered if targeting of the key repair protein RAD51 could sensitize these cells. Utilizing a validated small molecule inhibitor of RAD51 (19), MDA-MB-231 RES were actually signi cantly more sensitive to the inhibitor than MDA-MB-231SENS cells (Fig. 3A).…”

Section: Sensitization Of Chemoresistant Cells By Targeting Rad51 Andmentioning

confidence: 99%

Genome Instability and Pressure on Non-Homologous end Joining drives Chemotherapy Resistance via a DNA Repair Crisis Switch in Triple Negative Breast Cancer.

Wiegmans

Ward

Ivanova

et al. 2020

Preprint

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Background: Chemotherapy intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of chemotherapy resistance and tailor patient staging appropriately. This is especially evident in the triple negative breast cancer (TNBC) subtype, of which standard of care is chemotherapy with tumours displaying high levels of inherent genome instability. TNBC has an overall poor prognosis for survival. There have been numerous studies into single agent chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. Methods: In this study, we hypothesized that the emergence of chemotherapy resistance is driven by changes in functional signaling in the DNA repair pathways. We identified the importance of the DNA repair pathways in chemoresistant clinical samples and characterized the emergence of chemoresistance in TNBC cell lines. We utilized classical DNA repair assays and specific targeting of key DNA repair proteins to elucidate a new mechanism for adaptation to the combination of doxorubicin and docetaxel. Results: We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurs to repair residual double strand DNA breaks. Conclusions: We demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination.

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Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

Abstract: Abbreviations: BRAC2, breast cancer type 2 susceptibility protein; GFP, green fluorescent protein; HR, homologous recombination; HTS, high throughput screening.

Cited by 19 publications

References 20 publications

Optimization of Drug Candidates That Inhibit the D‐Loop Activity of RAD51

Optimization of Drug Candidates That Inhibit the D‐Loop Activity of RAD51

Quinazolinone and Quinazoline Derivatives: Synthesis and Biological Application

Genome Instability and Pressure on Non-Homologous end Joining drives Chemotherapy Resistance via a DNA Repair Crisis Switch in Triple Negative Breast Cancer.

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