Interleukin-1 receptor-associated kinase 4 (IRAK4) is the most upstream kinase in Toll/Interleukin-1 receptor (TIR) signaling[2]. In the chronic ethanol-induced liver injury mouse model, hepatic inflammation and hepatocellular damage were attenuated in Irak4 KI mice. IRAK4 kinase activity promotes expression of acute phase proteins in response to ethanol exposure, including C-reactive protein and serum amyloid A1 (SAA1). SAA1 and IL-1β synergistically exacerbate ethanol-induced cell death ex vivo. Pharmacological blockage of IRAK4 kinase abrogated ethanol-induced liver injury, inflammation, steatosis, as well as acute phase gene expression and protein production in mice[3]. IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression[4]. Emavusertib (CA-4948) is a potent IRAK4/FLT3 inhibtor with anti-tumor activity[5]. CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia[1].
Emavusertib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Karpas1718
3.72 μM (IC50)
72 hours
To evaluate the antiproliferative activity of Emavusertib as a single agent in MYD88 L265P-mutated MZL cell lines. Results showed that Karpas1718 cells were most sensitive to Emavusertib with an IC50 of 3.72 μM.
J Clin Med. 2023 Jan 4;12(2):399
SKM-1
50-250 nM
20 hours
increased cell viability
Curr Issues Mol Biol. 2024 Mar 29;46(4):2946-2960
OCI-AML3
50-250 nM
20 hours
increased cell viability
Curr Issues Mol Biol. 2024 Mar 29;46(4):2946-2960
ML-2
50-250 nM
20 hours
increased cell viability
Curr Issues Mol Biol. 2024 Mar 29;46(4):2946-2960
VL51
21-38 μM (IC50)
72 hours
To evaluate the antiproliferative activity of Emavusertib as a single agent in VL51 cell line and its derivatives. Results showed that VL51 cells and their derivatives were less sensitive to Emavusertib with IC50 values ranging from 21-38 μM.
J Clin Med. 2023 Jan 4;12(2):399
MOLM-13
50-250 nM
20 hours
induced cell cycle arrest, apoptosis and cell death
Curr Issues Mol Biol. 2024 Mar 29;46(4):2946-2960
Emavusertib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
MDS patient-derived xenograft model
Oral
12.5 mg/kg/d
5 times a week for 3-4 weeks
To evaluate the effect of IRAK4 inhibitor CA-4948 on MDS clone growth. Results showed that CA-4948 significantly reduced MDS clone growth.
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