Question

An ATP competitive inhibitor that is designed as an IRAK4 selective compund has an IC50 of 20nM for IRAK4. Two other kinases that show high similarity at the ATP binding site to IRAK4 are ROCK I and II. To investigate the selectivity of this compound, potencies were measured against a panel of kinases. These measurmens were done under the same experimenetal conditions. IC50's for ROCK I and II were measured to be 100 nM. Do you predict this compund to be IRAK4 or ROCK I & II selective in vivo? Please explain your answer.

Answer 1

By definition, IC50 is a concentration of inhibitor where its response to binding to any substrate is reduced to half. Or half potency to work in simple terms

Now in our case, ATP inhibitor (designed) for IRAK4, has IC50 = 20nM

And in case of two new compounds, ROCK1 and 2, the IC50 for these against IRAK4 is 100nM

Now if you deduce the above information,

When IRAK4 is inhibited by the new compound it has some value of concentration on which is inhibits it, and if this binding is reduced to 50%, then the concentration value is given as 20nM

And when ROCK1/2 is inhibited by this new compound, and binding is reduced to 50% then the concentration value for compound is given as 100nM,

so overall, it take more concentration of desigend drug to reduced its efficiency for ROCK1/2 than to that of IRAK4.

Since in-vivo, all the inhibition take place at minimum concentration of inhibitors in biological systems. So for IRAK4 inhibition by compund is require less concentration, IRAK4 will be selected for the inhibition by the newly designed compound.

Just the 20nM concentration, 50% of inhibition can be done by the new compound for IRAK4.

so its IRAK4 selective in-vivo.