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9 results on '"Noronha, Glenn"'

1. Primary Cell Experiments with TG101348, a JAK2-Selective Inhibitor, in the Presence of Myeloproliferative Disorder-Associated JAK2V617F, MPLW515L/K, and JAK2 Exon 12 Mutations.

Author

Lasho, Terra L., primary, Finke, Christy, additional, Hood, John D., additional, Soll, Richard, additional, Noronha, Glenn, additional, Mesa, Ruben A., additional, Jamieson, Catriona, additional, Verstovsek, Srdan, additional, Cortes, Jorge, additional, Kantarjian, Hagop, additional, Gilliland, D. Gary, additional, Tefferi, Ayalew, additional, and Pardanani, Animesh, additional

Published
2007
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2. Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia Vera.

Author

Wernig, Gerlinde, primary, Kharas, Michael G., additional, Okabe, Rachel, additional, Moore, Sandra A., additional, Leeman, Dena S., additional, Cullen, Dana E., additional, Gozo, Maricel, additional, McDowell, Elizabeth P., additional, Levine, Ross L., additional, Doukas, John, additional, Mak, Chi Ching, additional, Noronha, Glenn, additional, Martin, Michael, additional, Ko, Yon D., additional, Lee, Benjamin H., additional, Soll, Richard, additional, Tefferi, Ayalew, additional, Hood, John D., additional, and Gilliland, D. Gary, additional

Published
2007
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5. TG101209, a Selective JAK2 Kinase Inhibitor, Suppresses Endogenous and Cytokine-Supported Colony Formation from Hematopoietic Progenitors Carrying JAK2V617F or MPLW515K/L Mutations.

Author

Pardanani, Animesh, primary, Hood, John, additional, Lasho, Terra, additional, Noronha, Glenn, additional, Finke, Christy, additional, Mak, Chi Ching, additional, Mesa, Ruben, additional, Zhu, Hong, additional, Soll, Richard, additional, and Tefferi, Ayalew, additional

Published
2006
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6. Inhibition of JAK2 V617F-Induced Erythroid Skewing of Hematopoietic Stem Cell Differentiation with a Selective JAK2 Antagonist.

Author

Geron, Ifat, primary, Barroga, Charlene, additional, Gotlib, Jason, additional, Kavalerchik, Edward, additional, Abrahamsson, Annelie, additional, Goff, Daniel, additional, Cacalano, Nicholas, additional, Hood, John, additional, Soll, Richard, additional, Noronha, Glenn, additional, Tefferi, Ayalew, additional, Weissman, Irving L., additional, Kaushansky, Kenneth, additional, and Jamieson, Catriona, additional

Published
2006
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7. In Vitro and In Vivo Inhibition of the T315I Mutant BCR/ABL Kinase.

Author

Zhu, Hong, primary, Hanna, Ehab, additional, Lohse, Dan, additional, Stoughton, Silva, additional, Tam, Betty, additional, Barrett, Kathy, additional, Noronha, Glenn, additional, Dneprovskaia, Elena, additional, Cao, Jon, additional, Chow, Chun, additional, Hwang, Linda, additional, Mak, Chiching, additional, McPherson, Andy, additional, Palanki, Moorthy, additional, Pathak, Ved P., additional, Renick, Joe, additional, Soll, Richard, additional, Zeng, Binqi, additional, and Hood, John, additional

Published
2006
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8. Prospective Identification of Resistance Mutants to the JAK2 Inhibitor TG101348

Author

Jon Cao, Marcela Alomia, John Hood, Noronha Glenn, Richard Soll, Hanna Ehab, Mak Chi Ching, Zhu Hong, McPherson Andy, Tam Betty, Chun Chow, and Lohse Dan

Subjects
Myeloid, Kinase, Point mutation, Immunology, Wild type, Cell Biology, Hematology, TG101348, Biology, medicine.disease, Biochemistry, JAK2 Inhibitor TG101348, Dasatinib, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, hemic and lymphatic diseases, medicine, Cancer research, medicine.drug, Chronic myelogenous leukemia
Abstract

Introduction: Clinical resistance to kinase inhibitors is an emerging theme in targeted, oncology therapies. For example, Gleevec resistance results due to a host of mutations in bcr-abl, the kinase associated with chronic myelogenous leukemia (CML), and have necessitated the development of 2nd generation inhibitors dasatinib and notilinib. More recently, mutations in JAK2 kinase have recently been identified as the key molecular drivers for the majority of patients with the chronic MPDs polycythemia vera, essential thrombocythemia and myelofibrosis with myeloid metaplasia. TG101348 is a selective inhibitor of JAK2 kinase and represents a novel therapy for these MPDs. Methods: In order to better understand what mutations may occur in clinic as a result of TG101348 treatment, we used N-ethyl-N-nitrosourea (ENU)-exposed human erythroleukemia (HEL) cells to evaluate resistance mutations to TG101348. In brief, ENU pretreated HEL cells were exposed to 3 uM TG101348, a dose that is 10X the cellular IC50, for 28 days followed by genotyping to determine the incidence and location of kinase domain mutants that arose in resistant cells. Results: Eleven different mutations were identified, with the most prevalent mutations in associated with the ATP binding pocket. In cells bearing these mutations TG101348 did not inhibit STAT5 phosphorylation, cellular proliferation or induced apoptosis at concentrations up to 3 uM, whereas in wildtype HEL cells it did. Consistent with the mutations arising specific for TG101348, JAK2 inhibitors which are derived from chemically distinct series were equally potent on wildtype or TG101348 resistant HEL cells. Conclusions: A series of JAK2 point mutations were identified which generate resistance to the JAK2 inhibitor TG101348 in JAK2V617F-bearing cells. None of these mutations corresponded to any mutations that have been previously reported for MPD patients and therefore the clinical relevance of these mutations is not yet known. While these ENU induced mutations do not yet have clinical correlates, monitoring for their presence in any patients who do not respond to TG101348 in clinical trials may shed light on mechanisms of resistance as they occur.

Published
2007

9. In Vitroand In VivoInhibition of the T315I Mutant BCR/ABL Kinase.

Author

Zhu, Hong, Hanna, Ehab, Lohse, Dan, Stoughton, Silva, Tam, Betty, Barrett, Kathy, Noronha, Glenn, Dneprovskaia, Elena, Cao, Jon, Chow, Chun, Hwang, Linda, Mak, Chiching, McPherson, Andy, Palanki, Moorthy, Pathak, Ved P., Renick, Joe, Soll, Richard, Zeng, Binqi, and Hood, John

Abstract

The T315I point mutation situated at the ATP-binding site of BCR/ABL tyrosine kinase remains to be the major unmet medical need in treating CML patients. None of the marketed CML drugs, including Imatinib or the recently approved Dasatinib, are able to inhibit this clinically most prevalent mutant of BCR/ABL kinase. To overcome the T315I mutation-presented hurdle, a novel small molecule BCR/ABL inhibitor, TG101223, has been synthesized and characterized in vitroand in vivo. Enzymatic activity of T315I mutant kinase and proliferation of BaF3:BCR/ABLT315Icells were inhibited with an IC50of 50 nM and EC50of 500 nM respectively. However, little effect of TG101223 was observed on the proliferation of the control BaF3 cells (IC50≥5,000 nM). Consistent with these observations, 24 hour treatment with 2,000 nM TG101223 induced DNA fragmentation in BCR/ABLT315Icells, but not in the control BaF3 cells. Furthermore, caspase-3 activation was detected in BCR/ABLT315Icells by an in-cell caspase assay following 4 h treatment with 2,000 nM TG101223. The above results strongly suggest that TG101223 inhibits BCR/ABLT315I-mediated cell proliferation and survival. In contrast, Imatinib did not inhibit AblT315Ienzyme nor BCR/ABLT315Icell proliferation. The kinase selectivity of TG101223 was determined using a commercial enzyme assay with a panel of 49 phylogentically diverse protein kinases. Only Abl, Flt3 and the mutants of those two kinases were inhibited by more than 80% with 500 nM TG101223. Importantly, TG101223 demonstrated a desirable pharmacokinetic profile in mouse (oral bioavailability: 40%, clearance: 23 mL/min/kg and T½: 5 h). The tumorogenicity of BCR/AblT315Icells were confirmed by the observation that tail vein infusion with BCR/ABLT315Icells induced splenomegaly in SCID mice and death by day 14. To assess the in vivoactivities of TG101223, mice were dosed orally once with TG101223 on day 13, followed by harvesting of their spleens 7 hours after dosing for Western blot-based protein phosphorylation analysis. A significant induction in phosphorylation of both CrkL and BCR/ABL was observed in the spleens of T315I cell recipient mice, supporting the notion that splenomegaly is a result of the infiltration of proliferating BCR/ABLT315Icells. The above induction in spleen CrkL and BCR/ABL phosphorylation was inhibited by TG101223. These data suggest that TG101223 is a promising candidate for treating the drug resistant CML patients.

Published
2006
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