Abstract 785: IRAK4 inhibitors display synergistic activity when combined with BTK or PI3K inhibitors in B cell lymphomas

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.785-785
• Main Authors: Vajda, Eric G., Niecestro, Robert, Zhi, Lin, Marschke, Keith B.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-785

Signaling mediated by interleukin receptor associated kinase 4 (IRAK4) may play a permissive role in certain B-cell lymphomas. In addition, activating mutations of MYD88, which is upstream of IRAK4, have been identified in various B cell malignancies such as DLBCL and WM. Furthermore, there is recent evidence that IRAK4 mediated signaling may work in conjunction with other pathways such involving Bruton's tyrosine kinase(BTK) and phosphoinositide 3-kinase (PI3K). We have identified novel small molecule inhibitors of IRAK1/4 that may be useful therapeutics for the treatment of B cell lymphomas. Lead compounds LG0224912 and LG0250276 were potent inhibitors of IRAK4 in kinase inhibition assays (IC50 = 0.7 nM and 2.9 nM, respectively). Compounds were found to be selective kinase inhibitors after screening in a panel of 381 kinases. Functional inhibition of the IL-1 pathway was determined in the A549 cell line which expresses high levels of IL-1R. A549 cells were stimulated overnight with interleukin-1 and interleukin-6 (IL-6) concentrations were measured by ELISA in the presence of inhibitors or controls. Both compounds inhibited IL-6 with an IC50