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Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

Protein-data-bank , Cancer-cell-line-encyclopedia , Extended-data , Supplementary-information , Extended-data-table , Horizon-oncosignature , Supplementary-table ,

New Pediatric Cancer Marker Boosts Hope for Treatment

New Pediatric Cancer Marker Boosts Hope for Treatment
miragenews.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from miragenews.com Daily Mail and Mail on Sunday newspapers.

San-francisco , California , United-states , Fresno , America , Julie-saba , Edna-beck , Swim-across-america-foundation , School-of-medicine , Pediatric-cancer-research , Broad-institute-cancer-cell-line-encyclopedia , University-of-california

Universal, essential biomarker identified for childhood neuroblastoma

Researchers have newly identified a universal, essential biomarker for the childhood cancer neuroblastoma – and a potential new target for treatment.

San-francisco , California , United-states , Julie-saba , Broad-institute-cancer-cell-line-encyclopedia , University-of-california , Broad-institute , Cancer-cell-line-encyclopedia , Dependency-map , Cancer , Iomarker , Rain

New pediatric cancer marker: Hope for a treatment target

New pediatric cancer marker: Hope for a treatment target
medicalxpress.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from medicalxpress.com Daily Mail and Mail on Sunday newspapers.

Julie-saba , Babak-oskouian , Broad-institute-cancer-cell-line-encyclopedia , Broad-institute , Cancer-cell-line-encyclopedia , Dependency-map ,

PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma

PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma
science.org - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from science.org Daily Mail and Mail on Sunday newspapers.

Proteostat-aggresome , Drug-administration , Celltiter-glo-luminescent-cell-viability , Gene-ontology , Drug-sensitivity , Cancer-therapeutics-response-portal , Cancer-cell-line-encyclopedia ,

Y chromosome proteins in female tissues

Y chromosome proteins in female tissues
science.org - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from science.org Daily Mail and Mail on Sunday newspapers.

Canada , Canadian , Canadian-institutes-of-health-research , National-heart , Blood-institute , Owens-family-foundation , European-commission , Brightfocus-foundation , Us-national-institutes-of-health , National-eye-institute , Canadian-institutes

BU study reveals crucial signaling pathway that drives head and neck cancers

Despite advances in defining the genomic characteristics of head and neck cancers, these malignancies continue to rank among the deadliest cancers with few targeted therapies available.

Lily-ramsey , Xaralabosg-varelas , Eric-reed , Mariaa-kukuruzinska , Stefano-monti , Tufts-university , Bu-chobanian-avedisian-school-of-medicine , Boston-university-chobanian-avedisian-school-of-medicine , School-of-medicine , Eisai-co-ltd-research-award , Research-scholar-award , Translational-research

Researchers shed light on signaling pathway responsible for head and neck cancers

Researchers shed light on signaling pathway responsible for head and neck cancers
medicalxpress.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from medicalxpress.com Daily Mail and Mail on Sunday newspapers.

Stefano-monti , Ericr-reed , Translational-research , Boston-university-chobanian-avedisian-school-of-medicine , School-of-medicine , Causal-inference-models , Interactions-between , Cell-states , Neck-cancer , Boston-university-chobanian , Avedisian-school , Cancer-genome-atlas

Immunotherapy in Renal Cell Carcinoma

Analyzing the genomic and transcriptomic data from multiple ccRCC datasets, including bulk-RNA sequencing and single-cell RNA sequencing data.

China , Rockville , Maryland , United-states , Germany , Shanghai , Beijing , San-diego , California , Cambridge , Cambridgeshire , United-kingdom

Cell line characterization and selection made easy

BioPharma

Jonathan-jacobs , Omicsoft-oncoland , Senior-director , Line-land , Soft-lands , Cancer-cell-line-encyclopedia , Biotech ,