CA-4948 is a selective and potent IRAK4 inhibitor which can be used as a therapeutic agent for hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling. CA-4948 exhibits favorable DMPK properties, oral bioavailability, and is well tolerated in mice. Furthermore, CA-4948 is previously shown to exhibit dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models
Interleukin-1 Receptor Associated Kinase-4 (IRAK-4) is a serine/threonine protein kinase belonging to tyrosine like kinase (TLK) family. It is one of the important signalling components downstream of IL-1/Toll family of receptors (IL-1R, IL-18R, IL-33R, Toll-like receptors) and plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways, IRAK-4 is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2.CA-4948, previously termed AU-4948, is a selective and potent IRAK4 inhibitor. According to data obtained from enzymatic assays, the inhibitory IC50 value of CA-4948 against human IRAK4 kinase is 37 nM. Moreover, CA-4948 showed high selectivity towards IRAK4 with kinase selectivity S35 score of 0.0343 at 1 μM. In vitro, CA-4948 inhibited ABC DLBCL OCI-LY10, SUDHL-2 and U2932 cells’ viability with IC50 values of 3.58 μM, 7.86 μM and 10.42 μM, respectively. The treatment time was 72 h, and cell viability was determined by a CellTiter-Glo method. In western blot analysis of a DLBCL cell line during a 20 min TLR-agonist stimulation, CA-4948 suppressed the phosphorylation level of IKK-β, NF-kB p65, and JNK at the concentration of 10 μM[1].
In ABC DLBCL OCI-LY3 xenograft model, CA-4948 administrated orally at the doses of 50 mg/kg or 150 mg/kg daily for more than 15 days resulted in tumor growth inhibition of 53% and 49%, respectively[1].
作用机制
CA-4948 is a potent and selective IRAK4 kinase inhibitor. According to docking mode study, CA-4948 anticipated to bind in ATP binding pocket close to gate-keeper Tyr262 residue in human IRAK4[1].
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