HG-12-6

HG-12-6 is a small-molecule inhibitor that bind preferentially to unphosphorylated IRAK4 with IC50 of 165.1 nM, displays 15-fold selectivity over phosphorylated IRAK4 (IC50=2876 nM); binds as type II inhibitor with IRAK4 in a “DFG-out” conformation.

Signaling Pathways >> Immunology/Inflammation >> IRAK

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> IRAK

IRAK4:165 nM (IC50, Unphosphorylated inactive IRAK4 )

IRAK4:2876 nM (IC50, Phosphorylated active IRAK4 )

The in-house compound HG-12-6 has a similar chemical scaffold as Ponatinib. The most differentiating components are the head of the inhibitor and the lack of a methyl substituent on ring A. Without the methyl substituent on ring A, the entire HG-12-6 molecule shifts inward to the ATP pocket in comparison with the binding mode of Ponatinib[1]. HG-12-6 has a better binding affinity for the unphosphorylated inactive IRAK4 kinase domain (IC50 of 165 nM) than the phosphorylated active IRAK4 kinase domain (IC50 of 2876 nM)[1].

[1]. Wang L, et al. Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4). J Biol Chem. 2019 Mar 22;294(12):4511-4519.