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Probe
IRAK4-IN-28 is in
the process of SERP review.
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commentary.
Potency assay (off target):
Millipore kinome selectivity for AZ1495 (%inhibition @ 0.1 μM) 275 kinase. The profile indicated (IRAK4 + 4/275 > 75%inh; 8/275 > 50%inh) showing inhibition of the CLK family (×3) and haspin kinase. These hits were followed up with concentration response data and confirmed inhibition of CLK1 (50 nM), CLK2 (5 nM), CLK4 (8 nM) and haspin (4 nM) together with other members of the IRAK family.
IRAK4-IN-28 has a short half-life of 2 h in rat when administered orally. There is not sufficient selectivity versus CLK4 (1,6 nM) and Haspin (0,8 nM) and the authors themselves state: "We considered whether any of the off-targets identified (CLK1, 2, 4 or haspin; Table 6) could be making a contribution to the observed efficacy. While it is not possible to rule this out, we were reassured by the subsequent in vivo profiling of additional in-house derived IRAK4 chemical equity with improved selectivity against these targets. These compounds produced similar findings to 28 both as single agent and in combination with ibrutinib, and we aim to publish these findings in due course.
(last updated:
22 Mar 2023 )
SERP+
Ratings
In Cell Rating
In Model Organisms
SERP+
Comments:
IRK4-IN-28 is a potent IRK4 Inhibitor in vitro and an effect on down-stream phosphorylation in cells was clearly shown at the recommended concentration. However, IRK-1 was identified as an off-target which should be considered for potential cellular experiments. Aside from IRK-1 and CLKs the selectivity profile over a large number of kinases (275), CYP450 Enzymes (5) and several ion channels can be considered as good.
