- Compound-1 was a potent ALK inhibitor (WT and mutant), with undesired inhibition of Aurora A kinase activity (implicated in cardio toxicity).
- From SBDD analysis, it was found proximity of pyrazole N2 nitrogen to catalytic Lys-162 of Aurora A (3Å distance) compared to ALK (4.4Å distance), was responsible for lack of selectivity.
- Disrupting the above interaction by having dimethyl pyrazole in compound-2, resulted in greater selectivity for Aurora A.
Ref: Bioorg. Med. Chem. Lett., 2013, 23, 4911