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Target Overview
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase that mediates immune signaling in innate immune and hematopoeitic stem cells and serves as a central mediator of toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) activation of downstream inflammatory and immune responses.1,2
In myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL), TLR and IL-1R pathways are frequently dysregulated, amplifying inflammatory and pro-leukemic signaling1. Mutations in splicing factor genes (such as U2AF1 and SF3B1) are common in MDS and drive expression of a hypermorphic IRAK4L isoform, that contributes to inflammatory pathway activation.3
Together, these features position IRAK4 as a critical disease node that sustains aberrant immune and survival signaling in myeloid and lymphoid malignancies, providing a compelling therapeutic target for interrupting pathogenic inflammation and oncogenic support.
Compound Overview
AZD2962 is a potent and IRAK4-selective inhibitor that is being evaluated in clinic for relapsed or refractory (R/R) MDS. AZD2962 aims to achieve a best-in-class risk/benefit profile (more specific and ~100X more potent than the competitor with a good safety profile) enabling greater exposure and thus greater efficacy with deeper responses.
Mechanism of Action
References
1. Wei Y, Dimicoli S, Bueso-Ramos C, et al. Leukemia. 2013;27(9):1832-1840. 2. Dimicoli S, Wei Y, Bueso-Ramos C, et al. PLoS One. 2013;8(8):e71120. 3. Varney ME, Niederkorn M, Konno H, et al. J Exp Med. 2015;212(11):1967-1985. 4. Barreyro L, Chlon TM, Starczynowski DT. Blood. 2018;132(15):1553-1560.
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Abbreviations
AML
acute myeloid leukemia
CMML
chronic myelomonocytic leukemia
IL-1R
interleukin-1 receptor
IRAK4
interleukin-1 receptor-associated kinase 4
IRAK4L
long isoform of interleukin-1 receptor-associated kinase 4
MDS
myelodysplastic syndromes
NHL
non-hodgkin lymphoma
R/R
relapsed or refractory
SF3B1
splicing factor 3b subunit 1
TLR
toll-like receptor
U2AF1
U2 small nuclear RNA auxiliary factor 1
Target Overview
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase that mediates immune signaling in innate immune and hematopoeitic stem cells and serves as a central mediator of toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) activation of downstream inflammatory and immune responses.1,2
In myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL), TLR and IL-1R pathways are frequently dysregulated, amplifying inflammatory and pro-leukemic signaling1. Mutations in splicing factor genes (such as U2AF1 and SF3B1) are common in MDS and drive expression of a hypermorphic IRAK4L isoform, that contributes to inflammatory pathway activation.3
Together, these features position IRAK4 as a critical disease node that sustains aberrant immune and survival signaling in myeloid and lymphoid malignancies, providing a compelling therapeutic target for interrupting pathogenic inflammation and oncogenic support.
Compound Overview
AZD2962 is a potent and IRAK4-selective inhibitor that is being evaluated in clinic for relapsed or refractory (R/R) MDS. AZD2962 aims to achieve a best-in-class risk/benefit profile (more specific and ~100X more potent than the competitor with a good safety profile) enabling greater exposure and thus greater efficacy with deeper responses.
Mechanism of Action
References
1. Wei Y, Dimicoli S, Bueso-Ramos C, et al. Leukemia. 2013;27(9):1832-1840. 2. Dimicoli S, Wei Y, Bueso-Ramos C, et al. PLoS One. 2013;8(8):e71120. 3. Varney ME, Niederkorn M, Konno H, et al. J Exp Med. 2015;212(11):1967-1985. 4. Barreyro L, Chlon TM, Starczynowski DT. Blood. 2018;132(15):1553-1560.
Clinical trial information
Select trial for more information
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Abbreviations
AML
acute myeloid leukemia
CMML
chronic myelomonocytic leukemia
IL-1R
interleukin-1 receptor
IRAK4
interleukin-1 receptor-associated kinase 4
IRAK4L
long isoform of interleukin-1 receptor-associated kinase 4
MDS
myelodysplastic syndromes
NHL
non-hodgkin lymphoma
R/R
relapsed or refractory
SF3B1
splicing factor 3b subunit 1
TLR
toll-like receptor
U2AF1
U2 small nuclear RNA auxiliary factor 1