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WRN dependency in dMMR/MSI-H endometrial cancer: Clinical perspectives of a novel synthetic lethality strategy.
Gynecol Oncol
March 2025
Unit of Gynecologic Oncology, IRCCS Humanitas Research Hospital, 20089, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy. Electronic address:
Synthetic lethality of mRNA quality control complexes in cancer.
Nature
February 2025
AbbVie, North Chicago, IL, USA.
Synthetic lethality exploits the genetic vulnerabilities of cancer cells to enable a targeted, precision approach to treat cancer. Over the past 15 years, synthetic lethal cancer target discovery approaches have led to clinical successes of PARP inhibitors and ushered several next-generation therapeutic targets such as WRN, USP1, PKMYT1, POLQ and PRMT5 into the clinic. Here we identify, in human cancer, a novel synthetic lethal interaction between the PELO-HBS1L and SKI complexes of the mRNA quality control pathway.
View Article and Find Full Text PDFPhosphorylation-dependent WRN-RPA interaction promotes recovery of stalled forks at secondary DNA structure.
Nat Commun
January 2025
Mechanisms, Biomarkers and Models Section - Genome Stability Group, Department of Environment and Health, Istituto Superiore di Sanità, Viale Regina Elena, 299 - 00161, Rome, Italy.
The WRN protein is vital for managing perturbed replication forks. Replication Protein A strongly enhances WRN helicase activity in specific in vitro assays. However, the in vivo significance of RPA binding to WRN has largely remained unexplored.
View Article and Find Full Text PDFQuinazoline 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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