DDR1-IN-1

DDR1-IN-1 has modest biochemical selectivity (4X) for DDR1 over DDR2, but shows excellent broader selectivity across the KinomeScan panel when tested at 1 uM (S(1) at 1 uM of 0.01). DDR1-IN-1 demonstrates only weak cellular potency (no antiproliferative effects at concentrations of <10 uM), and it is not clear if this is a limitation of the compound or reflective of the target biology. Positive combination effects are seen with other kinase inhibitors, such as GSK2126458 (a PI3K/mTOR inhibitor), implying that the compound is capable of engaging its target in cells. For now, DDR1-IN-1 appears to be an acceptable probe for DDR1-dependent signal transduction.

DDR1-IN-1 is selective across 451 kinases with selectivity score (S(1) at 1 uM) of 0.01, as assessed with the KinomeScan approach. It is more effective in combination with inhibitors against EGFR, SRC, CDK1, mTOR and PI3K, for example with GSK212458. The PK profile is modest with t_1/2 = 2.76 hrs; C_L = 89.88 (mL/min/kg); Vss = 18.02; and F = 26%. The compound is commercially available and accessible synthetically through a four step synthesis. X-ray crystal structure shows DDR1-IN-1 bound to DDR1 in the hinge binding area.