Dual Inhibition of Bruton’s Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin’s B Cell Malignancies

dc.contributor.authorAlfaro, Jennifer
dc.contributor.authorde Arce, Felipe Pérez
dc.contributor.authorBelmar, Sebastián
dc.contributor.authorFuentealba, Glenda
dc.contributor.authorAvila, Patricio
dc.contributor.authorUreta, Gonzalo
dc.contributor.authorFlores, Camila
dc.contributor.authorAcuña, Claudia
dc.contributor.authorDelgado, Luz
dc.contributor.authorGaete, Diana
dc.contributor.authorPujala, Brahmam
dc.contributor.authorBarde, Anup
dc.contributor.authorNayak, Anjan K.
dc.contributor.authorUpendra T.V.R.
dc.contributor.authorPatel, Dhananjay
dc.contributor.authorChauhan, Shailender
dc.contributor.authorSharma, Vijay K.
dc.contributor.authorKanno, Stacy
dc.contributor.authorAlmirez, Ramona G.
dc.contributor.authorHung, David T.
dc.contributor.authorChakravarty, Sarvajit
dc.contributor.authorRai, Roopa
dc.contributor.authorBernales, Sebastián
dc.contributor.authorQuinn, Kevin P.
dc.contributor.authorPham, Son M.
dc.contributor.authorMcCullagh, Emma
dc.date.accessioned2024-05-30T17:30:09Z
dc.date.available2024-05-30T17:30:09Z
dc.date.issued2017-05
dc.descriptionIndexación: Scopus
dc.description.abstractAlthough new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin’s lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton’s tyrosine kinase and phosphatidylinositol-3-kinase d, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
dc.description.urihttps://jpet.aspetjournals.org/content/361/2/312
dc.identifier.citationJournal of Pharmacology and Experimental Therapeutics Volume 361, Issue 2, Pages 312 - 3211 May 2017
dc.identifier.doi10.1124/JPET.116.238022
dc.identifier.issn0022-3565
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/57207
dc.language.isoen
dc.publisherAmerican Society for Pharmacology and Experimental Therapy (ASPET)
dc.rights.licenseCC BY 4.0 DEED Atribución 4.0 Internacional
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.titleDual Inhibition of Bruton’s Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin’s B Cell Malignancies
dc.typeArtículo
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