PT  - JOURNAL ARTICLE
AU  - Jennifer Alfaro
AU  - Felipe Pérez de Arce
AU  - Sebastián Belmar
AU  - Glenda Fuentealba
AU  - Patricio Avila
AU  - Gonzalo Ureta
AU  - Camila Flores
AU  - Claudia Acuña
AU  - Luz Delgado
AU  - Diana Gaete
AU  - Brahmam Pujala
AU  - Anup Barde
AU  - Anjan K. Nayak
AU  - T. V. R. Upendra
AU  - Dhananjay Patel
AU  - Shailender Chauhan
AU  - Vijay K. Sharma
AU  - Stacy Kanno
AU  - Ramona G. Almirez
AU  - David T. Hung
AU  - Sarvajit Chakravarty
AU  - Roopa Rai
AU  - Sebastián Bernales
AU  - Kevin P. Quinn
AU  - Son M. Pham
AU  - Emma McCullagh
TI  - Dual Inhibition of Bruton’s Tyrosine Kinase and Phosphoinositide-3-Kinase p110<em>δ</em> as a Therapeutic Approach to Treat Non-Hodgkin’s B Cell Malignancies
AID  - 10.1124/jpet.116.238022
DP  - 2017 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 312--321
VI  - 361
IP  - 2
4099  - http://jpet.aspetjournals.org/content/361/2/312.short
4100  - http://jpet.aspetjournals.org/content/361/2/312.full
SO  - J Pharmacol Exp Ther2017 May 01; 361
AB  - 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 δ, 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.