DDR1-IN-2 is a selective DDR1 inhibitor with IC50 value of 6.8nM in an enzymatic activity assay. It exhibited less inhibitory effect on DDR2 with IC50 value of 101.4nM. DDR1-IN-2 dose-dependently inhibited phosphorylation of DDR1 in NCI-H23 non-small cell lung cancer cells (NSCLC) expressing high level of DDR1 at doses of 0.5, 1 and 2μM. The inactivation of DDR1 by DDR1-IN-2 induced significant decrease of total protein levels of Bcl-xL and MMP-2. It suppressed the growth of A549, NCI-H23 and NCI-H460 human NSCLC cells with IC50 values of 2.7, 2.1 and 3.0μM, respectively, while the value in K562 human CML cells was approximately 0.038μM. Also it inhibited colony formation by NCI-H23 NSCLC cells with IC50 values of 0.56 and 3.29 μM, respectively. DDR1-IN-2 potently inhibited cell-matrix adhesion by ~17%, ~40% or ~88% at 5.0, 10.0 or 20.0 μM for 2 hours, respectively, as well as inhibited the invasiveness of NCI-H23 cells by ~30%, ~37% or ~82% at 1.0, 2.0 or 5.0 μM for 24 hours, respectively. DDR1-IN-2 possessed good PK profiles with oral bioavailability of 67.4%[2].
作用机制
DDR1-IN-2 tightly binds to the ATP-binding site of DDR1. It inhibited DDR1 in a competitive manner.[2]
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