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Emavusertib

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Chemical Structure| 1801344-14-8 同义名 : CA-4948
CAS号 : 1801344-14-8
货号 : A1152397
分子式 : C24H25N7O5
纯度 : 99%+
分子量 : 491.499
MDL号 : MFCD32693907
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(101.73 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
描述 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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.03mL

0.41mL

0.20mL

10.17mL

2.03mL

1.02mL

20.35mL

4.07mL

2.03mL
参考文献

[1]Bhumireddy A . Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. Chemistry Letters, 2020, 11(12).

[2] William T McElroy. Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018). Expert Opin Ther Pat. 2019 Apr;29(4):243-259.

[3]Han Wang,et al. Inhibition of IRAK4 kinase activity improves ethanol-induced liver injury in mice. J Hepatol. 2020 Dec;73(6):1470-1481.

[4]Qiong Li,et al. IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer. JCI Insight. 2019 Oct 3;4(19):e130867.

[5]Wiese MD, et al. Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs. 2020 Apr 17:1-8.