A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer

Li, Guodong; Henry, Stuart Adam; Líu, Hao; Kang, Tian-Shu; Nao, Sang-Cuo; Zhao, Yichao; Wu, Cheng‐Shyong; Jin, Jianwen; Zhang, Jiatong; Leung, Chung‐Hang; Chan, Philip Wai Hong; Edmond, Dik-Lung

doi:10.1039/c9sc05623h

Cited by 27 publications

(17 citation statements)

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“…[17][18][19] The MS and HPLC methods have high backgrounds resulting from articial DNA damage during complex sample preparation. 20,21 Alternatively, several new methods, including colorimetric, 22 electrochemical, 23 uorescent, 10,15,24,25 and luminescent assays, [26][27][28] have been developed. The colorimetric assay enables the visualized detection of hOGG1 activity, 22 but the preparation of DNA-AuNP probes is timeconsuming and laborious.…”

Section: Introductionmentioning

confidence: 99%

“…The uorescent assay utilizes 8-oxoG repair-induced assembly of a quantum dot-based nanosensor to detect hOGG1 activity, 10 but the intricate probe modications and costly uorescent nanomaterials limit its wide application. The luminescent assays based on the combination of DNA repair-response cleavage with the G-quadruplex-selective iridium(III) complex 26,28 and in vitro green uorescent protein expression 27 enable the detection of DNA repair enzyme activity 26 and inhibitor screening, 27,28 with distinct advantages of easy probe preparation, simple strategy, and low cost compared with the uorescent assays. However, due to the lack of target amplication, the improvement in sensitivity is not signicant for luminescent assays.…”

Section: Introductionmentioning

confidence: 99%

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A controlled T7 transcription-driven symmetric amplification cascade machinery for single-molecule detection of multiple repair glycosylases

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A controlled T7 transcription-driven symmetric amplification cascade machinery for single-molecule detection of multiple repair glycosylases

et al. 2021

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“…To investigate the ability of 1 to target Keap1 and Nrf2 in cellulo , the cellular thermal shift assay (CETSA) was conducted ( Fig. 3 A) [ 83 , 84 ]. Complex 1 significantly stabilized Keap1 and shifted the Keap1 melting curve by ca.…”

Section: Resultsmentioning

confidence: 99%

A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1–Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury

Líu

Feng

et al. 2021

Redox Biology

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Hepatotoxicity caused by an overdose of acetaminophen (APAP) is the leading reason for acute drug-related liver failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein that helps to regulate redox homeostasis and coordinate stress responses via binding to the Kelch-like ECH-associated protein 1 (Keap1). Targeting the Keap1-Nrf2 interaction has recently emerged as a potential strategy to alleviate liver injury caused by APAP. Here, we designed and synthesized a number of iridium (III) and rhodium (III) complexes bearing ligands with reported activity against oxidative stress, which is associated with Nrf2 transcriptional activation. The iridium (III) complex 1 bearing a bioactive ligand 2,9-dimethyl-1,10-phenanthroline and 4-chloro-2-phenylquinoline, a derivative of the bioactive ligand 2-phenylquinoline, was identified as a direct small-molecule inhibitor of the Keap1–Nrf2 protein-protein interaction. 1 could stabilize Keap1 protein, upregulate HO-1 and NQO1, and promote Nrf2 nuclear translocation in normal liver cells. Moreover, 1 reversed APAP-induced liver damage by disrupting Keap1–Nrf2 interaction and without inducing organ damage and immunotoxicity in mice. Our study demonstrates the identification of a selective and efficacious antagonist of Keap1–Nrf2 interaction possessed good cellular permeability in cellulo and ideal pharmacokinetic parameters in vivo , and, more importantly, validates the feasibility of conjugating metal complexes with bioactive ligands to generate metal-based drug leads as non-toxic Keap1–Nrf2 interaction inhibitors for treating APAP-induced acute liver injury.

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“…Recently, virtual screening has been employed for identifying inhibitors of cancer targets ( Zhong et al, 2016 ; Li et al, 2020 ). For example, Russo Spena et al (2019) identified VS10 as a selective PIN1 inhibitor with anti-ovarian cancer activity through virtual screening.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitination Regulators Discovered by Virtual Screening for the Treatment of Cancer

Song

et al. 2021

Front. Cell Dev. Biol.

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The ubiquitin-proteasome system oversees cellular protein degradation in order to regulate various critical processes, such as cell cycle control and DNA repair. Ubiquitination can serve as a marker for mutation, chemical damage, transcriptional or translational errors, and heat-induced denaturation. However, aberrant ubiquitination and degradation of tumor suppressor proteins may result in the growth and metastasis of cancer. Hence, targeting the ubiquitination cascade reaction has become a potential strategy for treating malignant diseases. Meanwhile, computer-aided methods have become widely accepted as fast and efficient techniques for early stage drug discovery. This review summarizes ubiquitination regulators that have been discovered via virtual screening and their applications for cancer treatment.

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A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer

Abstract: The discovery of UDG inhibitors against prostate cancer by using a robust photoluminescence screening assay that can avoid false negatives arising from the background fluorescence.

Cited by 27 publications

References 100 publications

A controlled T7 transcription-driven symmetric amplification cascade machinery for single-molecule detection of multiple repair glycosylases

A controlled T7 transcription-driven symmetric amplification cascade machinery for single-molecule detection of multiple repair glycosylases

A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1–Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury

Ubiquitination Regulators Discovered by Virtual Screening for the Treatment of Cancer

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