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

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 recen...

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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.
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description 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
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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&lt;100 nM. The anti-proliferative effects of IRAK4 inhibitors were examined in B cell lymphoma cell lines. We tested cell lines containing activating L265P mutation in MYD88 (OCI-LY3 and MWCL1 cell lines) or wild type MYD88 (OCI-LY19 and U266). In all 4 cell lines, IRAK4 inhibitors demonstrated anti-proliferative activity (IC50s ranged from 300 nM - 10 μM). The compounds had varying degrees of activity, but the activity of each compound was relatively consistent among the 4 cell lines. In contrast to previous reports, the in vitro activities of IRAK4 inhibitors were unaffected by the MYD88 mutation. Additional synergism studies were performed with IRAK4 inhibitors combined with either the BTK inhibitor ibrutinib or the PI3K inhibitors idelalisib and TGR-1202. The anti-proliferative effects of drug combinations were measured and a combination index (CI) was calculated using the Chou-Talalay method. Combination treatment of LG0250276 and ibrutinib resulted in a CI of 0.67 indicating moderate synergism in the OCI-LY19 cell line. Combination treatment of LG0250276 and idelalisib demonstrated even greater synergism with a calculated CI of 0.25 in the OCI-LY19 cell line. Comparable results were observed in combinations of LG0250276 with TGR-1202. Similar results were observed in combination studies with the OCI-LY3 cell line. The results suggest that IRAK4 inhibition may have synergistic effects when combined with BTK or PI3K inhibitors in B cell lymphomas irrespective of the MYD88 mutation status. Citation Format: Eric G. Vajda, Robert Niecestro, Lin Zhi, Keith B. Marschke. IRAK4 inhibitors display synergistic activity when combined with BTK or PI3K inhibitors in B cell lymphomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. 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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&lt;100 nM. The anti-proliferative effects of IRAK4 inhibitors were examined in B cell lymphoma cell lines. We tested cell lines containing activating L265P mutation in MYD88 (OCI-LY3 and MWCL1 cell lines) or wild type MYD88 (OCI-LY19 and U266). In all 4 cell lines, IRAK4 inhibitors demonstrated anti-proliferative activity (IC50s ranged from 300 nM - 10 μM). The compounds had varying degrees of activity, but the activity of each compound was relatively consistent among the 4 cell lines. In contrast to previous reports, the in vitro activities of IRAK4 inhibitors were unaffected by the MYD88 mutation. Additional synergism studies were performed with IRAK4 inhibitors combined with either the BTK inhibitor ibrutinib or the PI3K inhibitors idelalisib and TGR-1202. The anti-proliferative effects of drug combinations were measured and a combination index (CI) was calculated using the Chou-Talalay method. Combination treatment of LG0250276 and ibrutinib resulted in a CI of 0.67 indicating moderate synergism in the OCI-LY19 cell line. Combination treatment of LG0250276 and idelalisib demonstrated even greater synergism with a calculated CI of 0.25 in the OCI-LY19 cell line. Comparable results were observed in combinations of LG0250276 with TGR-1202. Similar results were observed in combination studies with the OCI-LY3 cell line. The results suggest that IRAK4 inhibition may have synergistic effects when combined with BTK or PI3K inhibitors in B cell lymphomas irrespective of the MYD88 mutation status. Citation Format: Eric G. Vajda, Robert Niecestro, Lin Zhi, Keith B. Marschke. IRAK4 inhibitors display synergistic activity when combined with BTK or PI3K inhibitors in B cell lymphomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. 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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&lt;100 nM. The anti-proliferative effects of IRAK4 inhibitors were examined in B cell lymphoma cell lines. We tested cell lines containing activating L265P mutation in MYD88 (OCI-LY3 and MWCL1 cell lines) or wild type MYD88 (OCI-LY19 and U266). In all 4 cell lines, IRAK4 inhibitors demonstrated anti-proliferative activity (IC50s ranged from 300 nM - 10 μM). The compounds had varying degrees of activity, but the activity of each compound was relatively consistent among the 4 cell lines. In contrast to previous reports, the in vitro activities of IRAK4 inhibitors were unaffected by the MYD88 mutation. Additional synergism studies were performed with IRAK4 inhibitors combined with either the BTK inhibitor ibrutinib or the PI3K inhibitors idelalisib and TGR-1202. The anti-proliferative effects of drug combinations were measured and a combination index (CI) was calculated using the Chou-Talalay method. Combination treatment of LG0250276 and ibrutinib resulted in a CI of 0.67 indicating moderate synergism in the OCI-LY19 cell line. Combination treatment of LG0250276 and idelalisib demonstrated even greater synergism with a calculated CI of 0.25 in the OCI-LY19 cell line. Comparable results were observed in combinations of LG0250276 with TGR-1202. Similar results were observed in combination studies with the OCI-LY3 cell line. The results suggest that IRAK4 inhibition may have synergistic effects when combined with BTK or PI3K inhibitors in B cell lymphomas irrespective of the MYD88 mutation status. Citation Format: Eric G. Vajda, Robert Niecestro, Lin Zhi, Keith B. Marschke. IRAK4 inhibitors display synergistic activity when combined with BTK or PI3K inhibitors in B cell lymphomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. 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