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Discovery and characterization of a novel WRN inhibitor

ABSTRACT: Discovery and characterization of a novel WRN inhibitor

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Hans Voshol

LAB HEAD: Johannes Voshol

PROVIDER: PXD044202 | Pride | 2024-01-31

REPOSITORIES: Pride

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			Action	DRS
	PXP0990_FR01_BLU1_2020_0480.raw	Raw
	PXP0990_FR02_BLU1_2020_0481.raw	Raw
	PXP0990_FR03_BLU1_2020_0482.raw	Raw
	PXP0990_FR04_BLU1_2020_0483.raw	Raw
	PXP0990_FR05_BLU1_2020_0485.raw	Raw

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1 - 5 of 26

Publications

Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

Ferretti Stephane S Hamon Jacques J de Kanter Ruben R Scheufler Clemens C Andraos-Rey Rita R Barbe Stephanie S Bechter Elisabeth E Blank Jutta J Bordas Vincent V Dammassa Ernesta E Decker Andrea A Di Nanni Noemi N Dourdoigne Marion M Gavioli Elena E Hattenberger Marc M Heuser Alisa A Hemmerlin Christelle C Hinrichs Jürgen J Kerr Grainne G Laborde Laurent L Jaco Isabel I Núñez Eloísa Jiménez EJ Martus Hans-Joerg HJ Quadt Cornelia C Reschke Markus M Romanet Vincent V Schaeffer Fanny F Schoepfer Joseph J Schrapp Maxime M Strang Ross R Voshol Hans H Wartmann Markus M Welly Sarah S Zécri Frédéric F Hofmann Francesco F Möbitz Henrik H Cortés-Cros Marta M

Nature 20240424 8011

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 throug ...[more]

PMID: 38658754

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Discovery and Characterization of Second-Generation BET Bromodomain Inhibitor RG6146

Project description:BET Bromodomain inhibition is an epigenetic therapy that is being assessed as an anti-cancer strategy. Herein, we report the structure and activity of RG6146, a novel second-generation clinical grade BET inhibitor that was derived by optimization of the prototypical tool compound JQ1. We demonstrate that RG6146 elicits potent anti-proliferative and pro-apoptotic effects in multiple pre-clinical models of hematologic malignancies, including multiple myeloma (MM) and B-cell lymphoma. We show that the anti-tumor effects of RG6146 correlated with robust modulation of oncogenic transcription that results in suppression of oncogenic transcription factors, such as MYC, as well as direct activation of the intrinsic apoptotic cascade. Subcutaneous or intraperitoneal administration of RG6146 to tumor-bearing mice was well tolerated and led to pronounced anti-tumor responses in both syngeneic and xenograft tumor models, respectively. Finally, we investigated the ability for RG6146 to augment the activity of other targeted therapies in vitro and in vivo, demonstrating clear combination activity with BCL-2 inhibitor Venetoclax and anti-PD-1/PD-L1 immune checkpoint blockade. Taken together, our data demonstrates the therapeutic potential of novel pan-BET inhibitor RG6146 in the treatment of hematologic malignancies and highlights multiple mechanism-based combination strategies to enhance anti-tumor activity.

2023-05-31 | GSE203004 | GEO

Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression

Project description:Interleukin 9 (IL-9) is a γc-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2–JAK3–STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and over- expression of BCL6 impaired Th9 differentiation. In contrast to IL-2, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6−/− cells, whereas Th9 differentiation was increased in Il21−/− or Il21r−/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6–STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process. Genome-wide transcription factors mapping and binding of STAT5B and STAT6 in mouse polarized Th9 cells treated with or without blocking antibodies to IL-2 (anti-IL-2). RNA-Seq is conducted in WT and Il2-/- mice.

2014-02-20 | E-GEOD-41317 | biostudies-arrayexpress

High-efficiency RNA cloning enables quantitative measurement of miRNA expression by deep sequencing

Project description:MiRNA-mediated regulation depends on the stoichiometry between miRNAs and their mRNA targets. To decipher dynamic function of this complex layer, it is critical to characterize individual miRNA species within a specific cellular context. Small RNA cloning followed by deep sequencing is uniquely positioned as a genome-wide profiling method to quantify miRNA expression with potentially unlimited dynamic range and provide single-nucleotide resolution for precise miRNA classification and de novo discovery. However, significant biases introduced by RNA ligation steps in the current RNA cloning protocol often lead to inaccurate miRNA quantification by >1000-fold deviation. As a result, it has greatly hindered the broad application of this method. Here we report a highly efficient RNA cloning method that achieves over 90% efficiency for both 5’ and 3’ ligations with diverse small RNA substrates. When applied to a pool of either equimolar or differentially mixed synthetic miRNAs, the deviation of the cloning frequency for each miRNA is minimized to less than 2-fold of the anticipated value. By using samples obtained from multiple tissues and cells, we further demonstrate the accurate quantification of miRNA expression over a dynamic range of four orders of magnitude. Our results also reveal that most cistronic miRNAs are expressed at similar levels and, in each cell population, miRNAs repress their cognate targets in a dosage dependent manner. Collectively, our high-efficiency RNA cloning method combining with deep sequencing establishes a cost-effective approach for accurate genome-wide miRNA profiling. We designed an artificial system composed of synthetic miRNAs for benchmarking biases in small RNA cDNA cloning for NGS.

2013-09-18 | E-GEOD-47858 | biostudies-arrayexpress

Stem cell quiescence acts as a tumor suppressor mechanism in hair follicle initiated squamous tumors

Project description:In many organs, adult stem cells are uniquely poised to serve as cancer cells of origin. In the epidermis, hair follicle stem cells (HFSCs) cycle through stages of quiescence (telogen) and proliferation (anagen) to drive hair growth. Within the hair follicle, HFSCs are capable of initiating squamous cell carcinoma, yet it is unclear how the hair cycle contributes to tumorigenesis. The data presented here show that HFSCs are unable to initiate tumors during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant to gain of oncogenes (Ras) or loss of tumor suppressors (p53). Instead, prolonged oncogenic stimuli only exert their effects when HFSC quiescence mechanisms are removed by normal HFSC activation. Furthermore, Pten activity is necessary for quiescence based tumor suppression, since Pten deletion alleviates this stem cell specific ability without affecting proliferation per se. Small RNAs were cloned from Trizol-lysed cells sorted from mouse skin and sequenced with the Illumina HiSeq2000.

2013-10-28 | E-GEOD-51765 | biostudies-arrayexpress

Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase.

Project description:Neuraminidase, an abundant glycoprotein on the influenza virus surface, plays crucial roles in virus replication. Targeting neuraminidase could be a splendid way for the prevention of the spread of influenza infections. Herein, we have identified an octapeptide (errKPAQP) from a synthesized peptide library, originating from mimicking the binding pocket of oseltamivir in neuraminidase, as a potent peptide neuraminidase inhibitor. The docking-based virtual studies showed that errKPAQP exhibited a strong binding affinity (a docking score of -20.03) and nanomolar affinity (11 nM) to influenza neuraminidase, and can inhibit neuraminidase activity at a concentration as low as 4.25 μM, leading to effective protection of MDCK cells from influenza virus-induced death and replication. Furthermore, errKPAQP presented low hemolytic activity, minimal cytotoxicity, and good pharmacokinetic characteristics, which are imperative for an anti-influenza drug. Importantly, errKPAQP was capable of reducing influenza virus-induced inflammation, the serious damage to the lung tissues, and mortality rates in infected mice, indicating that it could protect against the lethal challenge of influenza viruses in vivo. Therefore, we have developed a novel neuraminidase peptide inhibitor with advantageous biological properties and high inhibitory activity towards neuraminidase, and it can serve as a promising anti-influenza drug.

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High-throughput SOLEXA sequencing of endogenous small RNAs from Arabidopsis thaliana wild-type

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2014-01-25 | E-GEOD-35335 | biostudies-arrayexpress

Complement factor B is critical for sub-RPE deposit formation in the Efemp1 R345W mutant mouse model with features of age-related macular degeneration

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2022-12-27 | GSE202777 | GEO

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