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GENE:

IRAK4 (Interleukin 1 Receptor Associated Kinase 4)

i
Other names: IRAK4, Interleukin 1 Receptor Associated Kinase 4, Interleukin-1 Receptor-Associated Kinase 4, Renal Carcinoma Antigen NY-REN-64, NY-REN-64, IRAK-4, IMD67, REN64, IPD1
Associations
Trials
4d
Fortunellin attenuates sepsis-induced acute kidney injury by inhibiting inflammation and ferroptosis via the TLR4/NF-κB pathway. (PubMed, Histol Histopathol)
Fortunellin ameliorates inflammation and oxidative stress in sepsis-induced AKI, possibly through the modulation of the TLR4/NF-κB pathway. These findings suggest fortunellin's potential as a therapeutic agent for sepsis-associated AKI.
Journal
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IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL1B (Interleukin 1, beta) • NFKBIA (NFKB Inhibitor Alpha 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
27d
Interleukin-1 Receptor-Associated Kinase 1 in Cancer Metastasis and Therapeutic Resistance: Mechanistic Insights and Translational Advances. (PubMed, Cells)
This review also covers the significance of IRAK1 in mediating cancer resistance to therapy and the underlying molecular mechanisms, including the evasion of apoptosis and maintenance of an inflammatory tumor microenvironment. Finally, we provide timely updates on the development of IRAK1-targeted therapy for human cancers.
Review • Journal • IO biomarker
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IL10 (Interleukin 10) • IL1R1 (Interleukin 1 receptor, type I) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • TRAF6 (TNF Receptor Associated Factor 6)
1m
Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches. (PubMed, Adv Biol Regul)
The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.
Journal
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SF3B1 (Splicing Factor 3b Subunit 1) • SRSF2 (Serine and arginine rich splicing factor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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SF3B1 mutation • SRSF2 mutation • U2AF1 mutation
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emavusertib (CA-4948)
1m
Methotrexate promotes the release of granulocyte-macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling. (PubMed, Arthritis Res Ther)
MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.
Journal
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CSF2 (Colony stimulating factor 2) • IL1A (Interleukin 1, alpha) • IL1B (Interleukin 1, beta) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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CSF2 expression
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methotrexate • tofacitinib • Kineret (anakinra)
2ms
Novel therapies for MDS and future prospects (PubMed, Rinsho Ketsueki)
This year, luspatercept, an anti-anemic agent targeting the TGFβ pathway, became available for clinical use in Japan. Various research initiatives are currently underway to develop new medicines targeting specific molecules within innate immune and inflammasome-signaling pathways, including IL-1β, CD33, TLR, IRAK4, and p38MAPK.
Journal
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CD33 (CD33 Molecule) • TGFB1 (Transforming Growth Factor Beta 1) • IL1B (Interleukin 1, beta) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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Reblozyl (luspatercept-aamt) • Rytelo (imetelstat)
2ms
Severe Invasive Infections Linked to Novel IRAK2 Immune Variants. (PubMed, Int J Infect Dis)
The result is impairment of the cytokine TNF-alpha production. This susceptibility to a varied range of pathogens underlines a potential central role played by IRAK2 in mediating host defense in infectious diseases.
Journal
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TNFA (Tumor Necrosis Factor-Alpha) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • TRAF6 (TNF Receptor Associated Factor 6)
2ms
Artemisinin attenuates perinatal inflammation and consequent oxidative stress in oligodendrocyte precursor cells by inhibiting IRAK-4 and IRAK-1. (PubMed, Int Immunopharmacol)
Our findings suggest that ART can significantly reduce OPC perinatal inflammation and consequent oxidative stress. The targeted inhibition of IRAK-4 and IRAK-1 by ART may be a potential therapeutic strategy for alleviating abnormalities in white matter development in premature newborns.
Journal
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IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL1B (Interleukin 1, beta) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
3ms
Activation of NF-κB/MAPK signaling and induction of apoptosis by salicylate synthase NbtS in Nocardia farcinica promotes neuroinflammation development. (PubMed, mSystems)
Given the rising importance of understanding host-microbe interactions within the context of the central nervous system, especially in immunocompromised individuals, the findings are of significant relevance to the field of microbiology and could inform future diagnostic and treatment modalities for Nocardia-associated neurological disorders. Our work emphasizes the need for continued research into the intricate mechanisms of microbial pathogenesis and the development of novel strategies to combat life-threatening infections.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • TNFA (Tumor Necrosis Factor-Alpha) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • TLR4 (Toll Like Receptor 4) • IL1B (Interleukin 1, beta) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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BAX expression
3ms
Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases. (PubMed, J Med Chem)
This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.
Journal
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IL1R1 (Interleukin 1 receptor, type I) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
3ms
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll-like receptors 4 and 7/8 in murine and human lungs. (PubMed, Br J Pharmacol)
These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7/8.
Preclinical • Journal
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TNFA (Tumor Necrosis Factor-Alpha) • TLR4 (Toll Like Receptor 4) • TLR8 (Toll Like Receptor 8) • TLR7 (Toll Like Receptor 7) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
4ms
Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages. (PubMed, Cell Rep)
In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.
Journal
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IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL1B (Interleukin 1, beta) • IFNB1 (Interferon Beta 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
5ms
Construction of IRAK4 inhibitor activity prediction model based on machine learning. (PubMed, Mol Divers)
Additionally, molecular dynamics simulations confirmed the stable binding of the screened compounds to the IRAK4 protein. Overall, this work presents a machine learning model for accurate prediction of IRAK4 inhibitor activity and offers new insights for subsequent structure-guided design of novel IRAK4 inhibitors.
Review • Journal • Machine learning
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IL1R1 (Interleukin 1 receptor, type I) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
5ms
IL-1 receptor-associated kinase family proteins: An overview of their role in liver disease. (PubMed, Eur J Pharmacol)
In this article, we provide a comprehensive review of the role of IRAK family proteins and their associated inflammatory signaling pathways in the pathogenesis of liver diseases. The purpose of this study is to explore whether IRAK family proteins can serve as the main target for the treatment of liver related diseases.
Review • Journal • IO biomarker
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IL1R1 (Interleukin 1 receptor, type I) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
5ms
Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma. (PubMed, J Med Chem)
KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IKZF1 (IKAROS Family Zinc Finger 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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KT-413
5ms
Advances in Targeted Therapies for Inflammatory Diseases and Cancer: Exploring Cellular Mechanisms and Therapeutic Strategies. (PubMed, ACS Med Chem Lett)
The first strategy involves proteolysis targeting chimeras (PROTACs) for the selective degradation of IRAK4, a kinase central to inflammatory signaling, the second employs lipid-binding protein complexes to modulate systemic inflammatory responses, and the third utilizes selective inhibitors targeting pathogenic epithelial stem cells to prevent the progression of metaplasia into dysplasia and cancer. Collectively, these approaches highlight a shift toward precision medicine, offering the potential for synergistic applications in clinical settings.
Journal
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IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
6ms
2,4'-Dihydroxybenzophenone: A Promising Anti-Inflammatory Agent Targeting Toll-like Receptor 4/Myeloid Differentiation Factor 2-Mediated Mitochondrial Reactive Oxygen Species Production during Lipopolysaccharide-Induced Systemic Inflammation. (PubMed, ACS Pharmacol Transl Sci)
The findings suggest that DHP exerts its anti-inflammatory effects by inhibiting the TLR4/MD2 signaling pathway and reducing the level of mtROS production. These results contribute to a better understanding of the biochemical properties of DHP and support its further exploration as a potential therapeutic agent for inflammatory conditions and endotoxemia.
Journal • IO biomarker
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • TNFA (Tumor Necrosis Factor-Alpha) • TLR4 (Toll Like Receptor 4) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
6ms
Transforming Therapeutic Approaches with PROTAC Technology: New Targets and Potentials. (PubMed, ACS Med Chem Lett)
By exploring the cutting-edge development of compounds targeting IRAK-4 and CDK2, this work illuminates PROTACs' role in treating immune disorders and cancer. The analysis not only highlights the specificity and potential of PROTACs in transforming disease treatment but also addresses the challenges and future directions of this technology, emphasizing its broad applicability and the promise of more effective therapeutic strategies.
Journal
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CDK2 (Cyclin-dependent kinase 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
7ms
Study of antitumor effects of human placenta hydrolysate on PC-3, OAW-42, BT-474 cell cultures (PubMed, Ter Arkh)
The results of the study indicate not only the oncological safety of the HPH used in therapy but also the mild antitumor effects of this HPH at high concentrations.
Preclinical • Journal
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PRKCH (Protein Kinase C Eta) • CDK1 (Cyclin-dependent kinase 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
7ms
Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation. (PubMed, J Med Chem)
Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.
Journal
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IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
7ms
FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (PubMed, Curr Issues Mol Biol)
The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.
Journal • Combination therapy • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NPM1 (Nucleophosmin 1) • CD34 (CD34 molecule) • ITGAM (Integrin, alpha M) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation
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Venclexta (venetoclax) • S63845 • emavusertib (CA-4948) • zelavespib intravenous (PU-H71 IV)
8ms
Toll-Like Receptor 4, 2, and Interleukin 1 Receptor Associated Kinase4: Possible Diagnostic Biomarkers in Myelodysplastic Syndrome Patients. (PubMed, Adv Biomed Res)
Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.
Journal • IO biomarker
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TLR4 (Toll Like Receptor 4) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • TLR2 (Toll Like Receptor 2)
8ms
Effectiveness of Narciclasine in Suppressing the Inflammatory Response in Sepsis: Molecular Docking and In Silico Studies. (PubMed, Bioinform Biol Insights)
Toxicity analysis by admetSAR revealed that narciclasine was readily biodegradable and exhibited minimum toxicity. These results indicate that narciclasine has effective anti-inflammatory properties which could be useful in suppressing the inflammatory response in sepsis.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • S100A8 (S100 Calcium Binding Protein A8) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
9ms
In vivo ablation of NFκB cascade effectors alleviates disease burden in myeloproliferative neoplasms. (PubMed, Blood)
Finally, pharmacological targeting of interleukin-1 receptor-associated kinase 4 (IRAK4) with inhibitor CA-4948 suppressed disease burden and inflammatory cytokines specifically in MPN without inducing toxicity in non-diseased models. These findings highlight vulnerabilities in MPN that are exploitable with emerging therapeutic approaches.
Preclinical • Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • RELA (RELA Proto-Oncogene)
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MPL W515L
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emavusertib (CA-4948)
11ms
A noncanonical IRAK4-IRAK1 pathway counters DNA damage-induced apoptosis independently of TLR/IL-1R signaling. (PubMed, Sci Signal)
The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.
Journal • IO biomarker
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TP53 (Tumor protein P53) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL1R1 (Interleukin 1 receptor, type I) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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TP53 mutation
11ms
Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy. (PubMed, J Pers Med)
The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.
Journal • IO biomarker
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IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
11ms
Novel IRAK4 Inhibitors for Treating Asthma, COPD, Cancer, Autoinflammatory Diseases, and Autoimmune Diseases. (PubMed, ACS Med Chem Lett)
Provided herein are novel IRAK4 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma, COPD, cancer, autoinflammatory diseases, and autoimmune diseases, and processes for preparing such compounds.
Journal
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IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
12ms
Application of PROTACs in Hematological Malignancies--Review (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)
Notably, PROTACs that target BCL-XL, IRAK4, STAT3 and BTK have entered clinical trials. The known PROTACs that have the potential to be used to treat various hematological malignancies are systematically summarized in this review.
Review • Journal
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BCL2L1 (BCL2-like 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
12ms
Trial in Progress: A Phase 1b Single-Arm, Open-Label Study of Emavusertib (CA-4948) in Combination with Azacitidine and Venetoclax in Acute Myeloid Leukemia Patients in Complete Response with Measurable Residual Disease (ASH 2023)
In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities.
Clinical • P1 data • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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Venclexta (venetoclax) • azacitidine • emavusertib (CA-4948)
12ms
Inhibition of Toll-like Receptor 4 (TLR4) Promotes Erythroid and Myeloid Differentiation in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) (ASH 2023)
Inhibition of the TLR4 pathway with a potent TLR4 antibody promotes erythroid and myeloid maturation and relieves the differentiation block on these lineages in MDS patient samples in the in vitro setting. Our preclinical data supports further evaluation of TLR4 inhibition as a therapeutic target in patients with MDS, as anemia and neutropenia are hallmarks of the disease.
IO biomarker
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TNFA (Tumor Necrosis Factor-Alpha) • CD34 (CD34 molecule) • LY9 (Lymphocyte Antigen 9) • S100A8 (S100 Calcium Binding Protein A8) • S100A9 (S100 Calcium Binding Protein A9) • CD14 (CD14 Molecule) • ITGAM (Integrin, alpha M) • TFRC • TLR4 (Toll Like Receptor 4) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • LY96 (Lymphocyte Antigen 96) • TRAF6 (TNF Receptor Associated Factor 6)
almost1year
Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization. (PubMed, Int Immunopharmacol)
CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CCR2 (C-C Motif Chemokine Receptor 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • IRF5 (Interferon Regulatory Factor 5)
1year
IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. (PubMed, Front Immunol)
These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.
Review • Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SF3B1 (Splicing Factor 3b Subunit 1) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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SF3B1 mutation • MYD88 L265P • U2AF1 mutation
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emavusertib (CA-4948)
1year
Caffeic acid phenethyl ester inhibits MDA-MB-231 cell proliferation in inflammatory microenvironment by suppressing glycolysis and lipid metabolism. (PubMed, Biomed Pharmacother)
After adding the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), the inhibitory effects of CAPE on cell viability and migration were not significant when compared with the LPS group. In summary, the antitumor activity of CAPE in vitro was mainly via the modulation of the inflammatory mediators and the inhibition of key proteins and enzymes in glucose and lipid metabolism.
Journal
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LDHA (Lactate dehydrogenase A) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CD36 (thrombospondin receptor) • TLR4 (Toll Like Receptor 4) • FASN (Fatty acid synthase) • HK2 (Hexokinase 2) • NFKBIA (NFKB Inhibitor Alpha 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • PKM (Pyruvate Kinase M1/2) • SLC2A1 (Solute Carrier Family 2 Member 1)
1year
Takeaim Lymphoma: An Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Combination with Ibrutinib in Patients with Relapsed or Refractory Hematologic Malignancies (ASH 2023)
The combination of emavusertib plus ibrutinib (ema+ibr) is well tolerated with an acceptable long-term safety profile and promising efficacy, showing several objective responses in heavily pretreated and/or BTK inhibitor resistant patients. Emavusertib may have the potential to overcome BTK inhibitor resistance and the combination of ema+ibr has the potential to show increased anti-cancer activity compared to ibrutinib monotherapy.
Clinical • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL1R1 (Interleukin 1 receptor, type I) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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Imbruvica (ibrutinib) • emavusertib (CA-4948)
1year
Kme-0584, a Highly Potent IRAK1/IRAK4/panFLT3 Inhibitor, Is a Promising Clinical Candidate for Hypomethylating Agent Plus Venetoclax Resistant AML/MDS Patients (ASH 2023)
In primary patient cell lines from FLT3 wildtype (WT) patients, KME-0584 inhibits leukemia stem cell progenitor function as measured by the colony formation assay in methylcellulose with higher potency than IRAK4 inhibitor compounds that lack IRAK1 activity such as CA-4948 (Emavusertib)...Given that monocytic-like subtypes of AML are resistant to Venetoclax plus Azacitidine (VEN/AZA) (S Pei et...KME-0584 exhibits superior potency and efficacy to gilteritinib in the FLT3-ITD (D835Y) xenograft model after QD oral dosing, with sufficient PK and oral bioavailability across multiple species to support QD or BID dosing in the clinic. KME-0584 does not inhibit any of the major or minor cytochrome P450 enzymes at anticipated clinical concentrations and early indication from ongoing GLP toxicology studies suggest that it could be safely administered in humans. A clinical study of KME-0584 in relapsed/refractory AML and HR-MDS is currently planned to start in 1H 2024.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • SF3B1 (Splicing Factor 3b Subunit 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • GLI2 (GLI Family Zinc Finger 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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FLT3 mutation • FLT3 D835Y • FLT3 D835 • U2AF1 mutation • FLT3 wild-type
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • emavusertib (CA-4948)
1year
In Vivo Ablation of NFκB Cascade Effectors Alleviates Disease Burden in Myeloproliferative Neoplasms (ASH 2023)
Through qRT-PCR and mass cytometry, we demonstrate that CA-4948 treatment dampened inflammatory cytokine production induced by IL-1β in primary MPN CD14+ monocytes. Overall, we demonstrate that targeting mediators including Rela, Myd88, and IRAK4 specifically alleviated MPN disease burden without toxicity to healthy tissue and further establish CA-4948 as a promising therapeutic avenue for the treatment of MPN.
Preclinical
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JAK2 (Janus kinase 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CHEK2 (Checkpoint kinase 2) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD14 (CD14 Molecule) • GPX4 (Glutathione Peroxidase 4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • IL1B (Interleukin 1, beta) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4) • RELA (RELA Proto-Oncogene) • TP53INP1 (Tumor Protein P53 Inducible Nuclear Protein 1)
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MPL W515L
|
emavusertib (CA-4948)
1year
Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress (ASH 2023)
R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract...The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase.
P1 data • IO biomarker
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TNFA (Tumor Necrosis Factor-Alpha) • TLR4 (Toll Like Receptor 4) • IL1R1 (Interleukin 1 receptor, type I) • NLRP3 (NLR Family Pyrin Domain Containing 3) • CRP (C-reactive protein) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
1year
Trial in Progress: An Open-Label Expansion Trial Evaluating the Safety, PK/PD, and Clinical Activity of Emavusertib (CA-4948) + Ibrutinib in R/R Primary CNS Lymphoma (ASH 2023)
Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.
Clinical • PK/PD data • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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MYD88 L265P
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Imbruvica (ibrutinib) • emavusertib (CA-4948)
1year
Pacritinib Blocks Key Pro-Survival Signaling Related to Mutated MYD88, Produces High Levels of Apoptosis and Overcomes Mutated BTKCys481 Related BTK-Inhibitor Resistance (ASH 2023)
We performed comparative studies to evaluate the activity of pacritinib and the covalent BTK-inhibitors ibrutinib and zanubrutinib on mutated MYD88 relevant pro-survival signaling, as well as proliferation and survival in MYD88 mutated cell lines and primary MYD88-mutated WM cells...Lastly, pacritinib alone and combined with venetoclax induced high levels of apoptosis in BTKCys481Ser expressing covalent BTK-inhibitor resistant MYD88 mutated WM and ABC DLBCL lymphoma cells... Pacritinib more broadly extinguishes mutated MYD88 pro-survival signaling cascades (Fig 1.) and demonstrates high levels of apoptotic activity in mutated MYD88 WM and ABC DLBCL cells versus selective covalent BTK-inhibitors. Pacritinib also synergizes with covalent BTK- and BCL2 inhibitors and can overcome covalent BTK-inhibitor resistance related to mutated BTKCys481. Our studies provide a framework for investigating pacritinib in MYD88 mutated lymphomas.
IO biomarker
|
MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SYK (Spleen tyrosine kinase) • IL6R (Interleukin 6 receptor) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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MYD88 mutation
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Vonjo (pacritinib)
1year
Preliminary Safety and Efficacy of Emavusertib (CA-4948) in Acute Myeloid Leukemia Patients with FLT3 Mutation (ASH 2023)
Two patients with prior gilteritinib exposure also received midostaurin therapy. In addition, mutational profiles are suggestive of disease-modifying activity of emavusertib. Enrollment in this trial is continuing at a dose of 300mg BID (phase 2 expansion cohort) for patients with ≤ 2 prior lines of therapy.
Clinical • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • SF3B1 (Splicing Factor 3b Subunit 1) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
|
FLT3-ITD mutation • FLT3 mutation • SF3B1 mutation • U2AF1 mutation
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Xospata (gilteritinib) • Rydapt (midostaurin) • emavusertib (CA-4948)
1year
Therapeutic Targeting of FLT3 Gate Keeper Mutation with E2082-0047 in Traditional and a Novel Immunocompetent Murine Adoptive Transfer Model of AML (ASH 2023)
Guided by KinomeScan data, we demonstrated simultaneous IRAK4 inhibition and verified superior in vivo efficacy compared to gilteritinib using the FLT3-ITD MOLM-13 cell line derived xenograft (CDX) murine model (Elgamal OA et al., ASH 2022). Given the curative potential of E2082-0047 in the immune competent model, ongoing efforts are focused on investigating the host immune response to AML. Given the safety and efficacy studies performed with E2082-0047 to date, a healthy volunteer study to best estimate dose for trials in AML is ongoing.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • FLT3-ITD F692L
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Xospata (gilteritinib)
1year
Synthetic Lethal Interactions with IRAK4 Inhibition in Myeloid Malignancies (ASH 2023)
In Phase-1 findings with a selective IRAK4 inhibitor (CA-4948; Curis Therapeutics), it was found that MDS and AML patients with splicing factor mutations responded best to monotherapy IRAK4 inhibition, although the overall response rate with monotherapy was modest...CC-90009 did not result in complete cell death up to concentrations of 10mM in both WT and IRAK4KO, suggesting that the selective sensitivity of IRAK4KO AML cells to CC-885 is not due to inhibition of GSPT1...These findings suggest that IRAK4 inhibition alters the pool of neosubstrates in AML cells for certain CELMoDs. Overall, our study demonstrates that IRAK4 is a therapeutic target in AML, but that combination therapies, such as with certain CELMoDs, will be necessary to achieve better clinical responses.
Synthetic lethality
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SF3B1 (Splicing Factor 3b Subunit 1) • IKZF1 (IKAROS Family Zinc Finger 1) • CRBN (Cereblon) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • IKZF3 (IKAROS Family Zinc Finger 3) • CASP3 (Caspase 3) • GSPT1 (G1 To S Phase Transition 1) • IKZF2 (IKAROS family zinc finger 2) • GLI2 (GLI Family Zinc Finger 2) • ANXA5 (Annexin A5) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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U2AF1 mutation
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emavusertib (CA-4948) • eragidomide (CC-90009)