Live & Let Dye: ERK Phosphorilation Inhibitors

Both small molecules 22 and 23 inhibited the proliferation
of several cancer cell lines, including HeLa cells with
IC50 values of around 15–20 mm, and A549 lung carcinoma cells
with IC50 values of 25 and 15 mm, respectively.


Given the finding that compound 22 binds directly to ERK2, the authors investigated the possible binding mode to the protein. The computational
screening applied at the onset of this research predicted
that 22 fits into the polar grove located between the
CD and ED sites on the ERK2 protein.


 More specifically, 22 appears to make contacts with several amino acid residues between
Asp316/Asp319 of the CD domain and Thr157/Thr158
of the ED domain. In particular, as well as a possible cation–p
interaction between Arg133 and the phenyl ring of 22, several
hydrogen bonds were observed between 22 and Asp316 and
Asp319.

It is likely that the amino group of 22 (protonated at
physiological pH) is engaged in salt bridges with Asp316 and
Asp319. Indeed, as well as taking advantage of its facile functionalization
towards structure optimization,


we are currently investigating the significance of the primary amine of 22 by introducing a variety of chemical modifications to reduce the
number of polar N H bonds and to alter the basicity of the nitrogen
atom; these results shall be reported in due course.