Biology Reference
In-Depth Information
Small Molecule Allosteric Modulators
of Phosphodiesterase 4
Mark E. Gurney, Alex B. Burgin, Olafur T. Magnusson,
and Lance J. Stewart
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
2 Structure of PDE4 Regulatory Domains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3 Fine Tuning of PDE4 Gating by Accessory Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
4 Active Site-Directed Competitive Inhibitors Bind an Open PDE4 Conformer . . . . . . . . . . . 177
5 UCR2-Directed Allosteric Modulators Bind an Asymmetric PDE4 Conformer . . . . . . . . . . 180
6 Improved Tolerability of UCR2-Directed, PDE4 Allosteric Modulators . . . . . . . . . . . . . . . . . 183
7 C-Terminal-Directed Inhibitors Bind a Closed, Symmetric PDE4 Conformer . . . . . . . . . . . 184
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Abstract Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human
clinical trials but dosing is limited by tolerability, particularly because of emesis.
Novel cocrystal structures of PDE4 catalytic units with their regulatory domains
together with bound inhibitors have revealed three different PDE4 conformers that
can be exploited in the design of novel therapeutic agents. The first is an open
conformer, which has been employed in the traditional approach to the design of
competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2
regulatory helix from one monomer is placed in a closed conformation over the
opposite active site in the PDE4 dimer (
trans
-capping). Only one active site can be
closed by an inhibitor at a time with the consequence that compounds exploiting
this conformer only partially inhibit PDE4 enzymatic activity while retaining
M.E. Gurney (
*
)
Tetra Discovery Partners, Grand Rapids, MI, USA
e-mail: mark@tetradiscovery.com
A.B. Burgin and L.J. Stewart
Emerald BioStructures, Bainbridge Island, WA, USA
O.T. Magnusson
deCODE genetics, Reykjavik, Iceland
