CAI Is a Potent Inhibitor of Neovascularization and Imparts Neuroprotection in a Mouse Model of Ischemic Retinopathy

2004 ◽  
Vol 45 (10) ◽  
pp. 3756 ◽  
Author(s):  
Alan J. Franklin ◽  
Tom L. Jetton ◽  
C. Lynn Kuchemann ◽  
Stephen R. Russell ◽  
Elise C. Kohn
Keyword(s):  
Mouse Model ◽  
Potent Inhibitor ◽  
Ischemic Retinopathy

scholarly journals High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
François Hermetet ◽  
Rony Mshaik ◽  
John Simonet ◽  
Patrick Callier ◽  
Laurent Delva ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Cell Surface ◽  
High Fat Diet ◽  
Myeloid Leukemia ◽  
Potent Inhibitor ◽  
Hematopoietic Cells ◽  
High Fat ◽  
Stat3 Signaling ◽  
Acute Myeloid

Abstract Using a MLL-AF9 knock-in mouse model, we discovered that consumption of a high-fat diet (HFD) accelerates the risk of developing acute myeloid leukemia (AML). This regimen increases the clusterization of FLT3 within lipid rafts on the cell surface of primitive hematopoietic cells, which overactivates this receptor as well as the downstream JAK/STAT signaling known to enhance the transformation of MLL-AF9 knock-in cells. Treatment of mice on a HFD with Quizartinib, a potent inhibitor of FLT3 phosphorylation, inhibits the JAK3/STAT3, signaling and finally antagonizes the accelerated development of AML that occurred following the HFD regimen. We can therefore conclude that, on a mouse model of AML, a HFD enforces the FLT3 signaling pathway on primitive hematopoietic cells and, in turn, improves the oncogenic transformation of MLL-AF9 knock-in cells and the leukemia initiation.

scholarly journals Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model

2016 ◽  
Vol 372 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Radhika Iyer ◽  
Lea Wehrmann ◽  
Rebecca L. Golden ◽  
Koumudi Naraparaju ◽  
Jamie L. Croucher ◽  
...  
Keyword(s):  
Mouse Model ◽  
Potent Inhibitor ◽  
Xenograft Mouse Model

scholarly journals A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia

2014 ◽  
Vol 459 (3) ◽  
pp. 427-439 ◽  
Author(s):  
Hanneke L. D. M. Willemen ◽  
Pedro M. Campos ◽  
Elisa Lucas ◽  
Antonio Morreale ◽  
Rubén Gil-Redondo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Present Article ◽  
P38 Mapk ◽  
Potent Inhibitor ◽  
Docking Site ◽  
Inflammatory Hyperalgesia ◽  
Analgesic Effects ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

We describe in the present article a novel family of docking site-based p38 MAPK inhibitors with good in vitro efficacy and long-lasting analgesic effects in a mouse model of persistent post-inflammatory hyperalgesia.

scholarly journals Hyperoxia Therapy of Pre-Proliferative Ischemic Retinopathy in a Mouse Model

2011 ◽  
Vol 52 (9) ◽  
pp. 6384 ◽  
Author(s):  
Wenbo Zhang ◽  
Harumasa Yokota ◽  
Zhimin Xu ◽  
Subhadra P. Narayanan ◽  
Lauren Yancey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Ischemic Retinopathy

scholarly journals The Bruton's Tyrosine Kinase (BTK) Inhibitor ARQ 531 Effectively Inhibits Wild Type and C481S Mutant BTK and Is Superior to Ibrutinib in a Mouse Model of Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3232-3232 ◽  
Author(s):  
Sean D. Reiff ◽  
Rose Mantel ◽  
Lisa L. Smith ◽  
Samantha McWhorter ◽  
Virginia M. Goettl ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mouse Model ◽  
Research Funding ◽  
Potent Inhibitor ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Wild Type ◽  
Bcr Signaling ◽  
Btk Inhibitor

Abstract Introduction: The Bruton's tyrosine kinase inhibitor ibrutinib improves survival in chronic lymphocytic leukemia (CLL) compared to standard chemotherapy or immune therapy. In a subset of patients, somatic mutation (C481S) of its binding site results in acquired resistance to ibrutinib therapy with poor clinical outcome. ARQ 531 is an ATP competitive, orally bioavailable, potent inhibitor of BTK and other relevant kinases including the majority of Src and Tec family kinases. Herein we present preclinical data with ARQ 531 in CLL including C481S mutated BTK and its efficacy versus ibrutinib in the TCL1 mouse model of CLL. Methods: Potency of ARQ 531 and its binding kinetics were measured in enzymatic and Surface Plasmon Resonance (SPR) binding assays. Primary CLL B cells were negatively selected and treated with 1μM ARQ 531. BCR signaling was investigated by immunoblot following a 1 hour drug incubation. CLL cells migrating towards CXCL12 and CXCL13 after 4 hours across a 5.0 micron transwell insert were counted by flow cytometry. Annexin V and propidium iodide flow cytometry was used to measure CLL viability over a range of drug concentrations and time. CpG mediated CLL cell activation was measured by CD40 and CD86 expression by flow cytometry. In vivo investigation utilized B6 mice engrafted with 1E7 CD5+/CD19+ TCL1 lymphocytes via tail vein injection. Mice were randomized to treatment with vehicle, ARQ 531, or ibrutinib following the establishment of a CD5+/CD19+ population >10% in peripheral blood. Results: At 72 hours the viability of CLL cells treated with 0.1µM, 1.0µM, or 10.0µM ARQ 531 was found to be 94%, 67%, and 50% that of untreated samples, respectively (p=0.76, p<0.001, p=0.016) in comparison to the 71% relative viability seen with 1µM ibrutinib (p<0.001). ARQ 531 demonstrates dose dependent inhibition of BTK, AKT, and ERK phosphorylation. Stimulation through TLR9 by CpG ligand increases expression of the activation markers CD40 and CD86; ARQ 531 decreased CpG induced expression of CD40 by 25% and CD86 by 40% (p=0.022, p=0.041). ARQ 531 in the presence of CXCL12 or CXCL13 decreased migration by 51% and 66%, respectively (p=0.015, p=0.025), below baseline migration of untreated CLL. Unlike ibrutinib, ARQ 531 inhibits both wild type and C481S BTK with an IC50 less than 1nM in a biochemical assay, and inhibits phosphorylation of C481S mutated BTK in LV125 transfected HEK293T cells. Cytotoxicity was also observed in CLL cells isolated from patients with C481S BTK mutations, where the viability of cells treated with 1µM ARQ 531 was 72% that of untreated cells at 72 hours (p=0.038). SPR binding assay showed a residence time of 51 minutes in wild type BTK and 56 minutes in C481S mutated BTK. The TCL1 mouse model displays active BCR signaling and responds to treatment with the BTK inhibitors ibrutinib and acalabrutinib (Ponader S, 2012; Herman SEM, 2015). Following establishment of leukemia in the TCL1 transfer model, we randomized mice to treatment with vehicle (n=14), 25 mg/kg ibrutinib (n=6), 50 mg/kg ARQ 531 (n=14) or 75 mg/kg ARQ 531 (n=14) given by daily gavage. ARQ 531 significantly improved survival over both ibrutinib and vehicle (median survival: 36 days vehicle, 53 days ibrutinib, not reached by 74 days 50mg/kg and 75 mg/kg ARQ 531, p<0.0001). Mice receiving ARQ 531 have consistently lower lymphocyte counts on microscopic examination and reduced CD5+/CD19+ populations via flow cytometry compared to vehicle or ibrutinib. Additionally, we have observed increases in absolute neutrophil count over time in mice receiving ARQ 531. Pharmacokinetic studies are pending; however, in a single oral dose study of 10mg/kg in monkeys, the bioavailability was 72.4% with a CMax of 9µM and a half-life greater than 24 hours. Conclusion: The BTK inhibitor ARQ 531 is a potent inhibitor of BTK with promising activity both in vitro and in vivo. Multi-targeted inhibition of cytokine, chemokine, and BCR pathways by ARQ 531 decreases activation, migration, and viability of CLL cells. Unlike ibrutinib, ARQ 531 inhibits activation of C481S mutated BTK variants and maintains cytotoxicity in ibrutinib resistant clones. Additionally, ARQ 531 has demonstrated remarkable efficacy in an in vivo TCL1 adoptive transfer model, improving survival to a greater extent than ibrutinib and potentially restoring granulocyte production. These data justify continued preclinical work and development to facilitate transition to clinical trials. Disclosures Eathiraj: ArQule, Inc: Employment. Abbadessa:ArQule, Inc: Employment. Schwartz:ArQule, Inc: Employment. Woyach:Acerta: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding.

scholarly journals Repurposing cytarabine for treating primary effusion lymphoma by targeting KSHV latent and lytic replications

2018 ◽  
Author(s):  
Marion Gruffaz ◽  
Shenghua Zhou ◽  
Karthik Vasan ◽  
Teresa Rushing ◽  
Qing Liu Michael ◽  
...  
Keyword(s):  
Mouse Model ◽  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Agent ◽  
Potent Inhibitor ◽  
Primary Effusion Lymphoma ◽  
Viral Dna ◽  
Dna And Rna ◽  
Virion Production ◽  
Novel Therapeutic

AbstractOncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically linked to primary effusion lymphoma (PEL), an aggressive and non-treatable malignancy commonly found in AIDS patients. In this study, we performed a high throughput screening of 3,731 characterized compounds, and identified cytarabine approved by FDA for treating numerous types of cancer as a potent inhibitor of KSHV-induced PEL. We showed the high efficacy of cytarabine in the growth inhibition of various PEL cells by inducing cell cycle arrest and apoptosis. Cytarabine inhibited host DNA and RNA syntheses and therefore induced cellular cytotoxicity. Furthermore, cytarabine inhibited viral DNA and RNA syntheses and induced the the rapid degradation of KSHV major latent protein LANA, leading to the suppression of KSHV latent replication. Importantly, cytarabine effectively inhibited active KSHV replication and virion production in PEL cells. Finally, cytarabine treatments not only effectively inhibited the initiation and progression of PEL tumors, but also induced regression of grown PEL tumors in a xenograft mouse model. Together, our study has identified cytarabine as novel therapeutic agent for treating PEL as well as eliminating KSHV persistent infection.ImportancePrimary effusion lymphoma is an aggressive malignancy caused by Kaposi’s sarcoma-associated herpesvirus. The outcome of primary effusion lymphoma is dismal without specific treatment. Through a high throughput screening of characterized compounds, we identified a FDA-approved compound cytarabine as a potent inhibitor of primary effusion lymphoma. We showed that cytarabine induced regression of PEL tumors in a xenograft mouse model. Cytarabine inhibited host and viral DNA and RNA syntheses, resulting in the induction of cytotoxicity. Of interest, cytarabine induced the degradation of KSHV major latent protein LANA, hence suppressing KSHV latent replication, which is required for PEL survival. Furthermore, cytarabine inhibited KSHV lytic replication program, preventing virion production. Our findings identified cytarabine as novel therapeutic agent for treating PEL as well as for eliminating KSHV persistent infection. Since cytarabine is already approved by the FDA, it might be an ideal candidate for repurposing for PEL therapy and for further evaluation in advanced clinical trials.

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