PDB Update

2E14 is ERK2 complexed to the macrocycle: FR-148083 via Astellas

BBRC: “Role of a cysteine residue in the active site of ERK and the MAPKK family”

related…

The Vertex J Med Chem

TM brought it up… So here’s my two cents on the latest Vertex J Med Chem.

TM thinks the pyrrol – pyrazoles are ubiquitous, and Vertex says: ‘Kinase activity of pyrazolylpyrroles has been reported previously.16-18′

16:Vertex; WO/2001/057022
17:Vertex; WO/2003/011854
18:Vertex; WO/2003/011855

But refs 16-18 are the apps which cover this series and that’s about it for the 3 pyrroles. The 2-pyrrole substructure can be seen all over the place from things like the DNA/Roche aurora indoles, to chk1, to plenty of others. A subtle difference, but all the difference given how these hit the ERK hinge.

Anyhow, in going after the ERK gatekeeper with the pyrrole, it is surprising to find JNK3 activity since the JNK gatekeeper is methionine rather then glutamine. Interestingly the ligand adopts a flipped conformation in JNK3 more reminiscent of what you’d expect from the pyrrol-2-yl-pyrazole, like indoles, benzimidazoles and such.

The way the paper is worded it seems as though the selectivity was worked out in advance of the structures being obtained. Heh.  If nothing else, the PDB’s give a good example of a pyrrole tightly hydrogen bound to GLN. 2OJG, 2OJI, 2OJJ, 2OK1,