Date: 2017-04-27
Type of
information: Publication of results in a medical journal
phase:
Announcement: publication of results in Nature
Company: Heptares Therapeutics (UK), a wholly-owned subsidiary of Sosei Group (Japan) AstraZeneca (UK)
Product: AZ8838, AZ3451
Action
mechanism: PAR2 antagonist. PAR2 is a G protein-coupled receptor (GPCR) that is a well-validated target for multiple indications in pain, cancer and inflammatory diseases, but which has previously proved to be intractable to conventional drug discovery approaches. PAR2 is an unusual GPCR that is activated by cleavage with a protease enzyme such that the cleaved part of the receptor acts as its own ligand. Because of this unusual mechanism of activation, it has been extremely difficult to identify PAR2 antagonists for development as new medicines.
Disease:
Therapeutic
area:
Country:
Trial
details:
Latest
news:
- • On April 27, 2017, Heptares Therapeutics announced the publication online in Nature of findings from the first resolved high-resolution X-ray crystal structures of the Protease-Activated Receptor-2 (PAR2) in complex with antagonist molecules.
- The Nature publication resulted from a long-term collaboration between scientists at Heptares and AstraZeneca, who have applied their respective technologies (including Heptares’ proprietary StaR® platform) and complementary discovery capabilities to identify several novel PAR2 antagonists. These antagonists were then crystallised in complex with the PAR2 receptor and their X-ray structures were elucidated with high resolution.
The structures have provided Heptares and AstraZeneca with a unique understanding of the precise mechanisms of action of these antagonists, which bind at novel allosteric sites distant from the ligand-binding site. In turn, these structural insights are providing a basis for further development of the small molecule drug candidates for a range of therapeutic indications. Specifically, the authors describe how the small molecule antagonist AZ8838, identified by AstraZeneca by high-throughput screening, binds to PAR2 in a fully occluded and previously inaccessible pocket near the extracellular surface of the receptor. A second molecule, AZ3451, identified by screening compounds with the PAR2-StaR® protein*, was found to bind a remote allosteric site that is thought to prevent structural rearrangements required for receptor activation and signalling.
The scientists also discovered that a blocking antibody fragment binds to the extracellular surface of the receptor to prevent access of the ligand to the binding site.
- (Cheng, RK et al. Structural insight into allosteric modulation of protease-activated receptor 2, (2017) Nature http://dx.doi.org/10.1038/nature22309).
Is
general: Yes
