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Specific Monitoring the DNA Helicase Function via Anchor-Embedded DNA Probe.
Adv Sci (Weinh)
December 2024
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
DNA helicases play a pivotal role in maintaining genome integrity by unwinding the DNA double helix and are often considered promising targets for drug development. However, assessing specific DNA helicase activity in living cells remains challenging. Herein, the first anchor-embedded duplex (ATED) probe, 17GC, is constructed to uniquely monitor the unwinding activity of Werner syndrome helicase (WRN), a clinical anticancer target.
View Article and Find Full Text PDFApplication and research progress of synthetic lethality in the development of anticancer therapeutic drugs.
Front Oncol
November 2024
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
With the tremendous success of the PARP inhibitor olaparib in clinical practice, synthetic lethality has become an important field for the discovery and development of anticancer drugs. More and more synthetic lethality targets have been discovered with the rapid development of biotechnology in recent years. Currently, many drug candidates that were designed and developed on the basis of the concept of synthetic lethality have entered clinical trials.
View Article and Find Full Text PDFMapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities.
Genome Med
November 2024
Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
Background: Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required.
Methods: Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types.
Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability.
Bioorg Chem
December 2024
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China. Electronic address:
WRN helicase is a crucial target of synthetic death in cancer and has a unique advantage in the treatment of microsatellite unstable cancers. Our previous studies have found that quinazoline derivatives showed the WRN-dependent antiproliferative activity. In this study, a series of new quinazoline derivatives were designed and synthesized by optimizing the structure, and evaluating the targeting and sensitivity to WRN helicase.
View Article and Find Full Text PDFDesign, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors.
Eur J Med Chem
January 2025
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address:
Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35.
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