1. Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110
- Author
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Jennifer, Alfaro, Felipe, Pérez de Arce, Sebastián, Belmar, Glenda, Fuentealba, Patricio, Avila, Gonzalo, Ureta, Camila, Flores, Claudia, Acuña, Luz, Delgado, Diana, Gaete, Brahmam, Pujala, Anup, Barde, Anjan K, Nayak, T V R, Upendra, Dhananjay, Patel, Shailender, Chauhan, Vijay K, Sharma, Stacy, Kanno, Ramona G, Almirez, David T, Hung, Sarvajit, Chakravarty, Roopa, Rai, Sebastián, Bernales, Kevin P, Quinn, Son M, Pham, and Emma, McCullagh
- Subjects
B-Lymphocytes ,Mice, Inbred BALB C ,Lymphoma, B-Cell ,Cell Death ,MAP Kinase Signaling System ,Adenine ,Lymphoma, Non-Hodgkin ,Receptors, Antigen, B-Cell ,Antineoplastic Agents ,Protein-Tyrosine Kinases ,Cell Line ,Mice ,Pyrimidines ,Piperidines ,Purines ,Agammaglobulinaemia Tyrosine Kinase ,Animals ,Humans ,Pyrazoles ,Phosphorylation ,Protein Kinase Inhibitors ,Phosphoinositide-3 Kinase Inhibitors ,Quinazolinones ,Signal Transduction - Abstract
Although 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
- Published
- 2016