Background: Extracellular signal-regulated kinase 5 (ERK5) is a member
of the protein kinase superfamily, which plays an essential role in the
transduction of extracellular signals to intracellular effectors. Activation of
the ERK5 signalling pathway is associated with cell survival, proliferation,
and differentiation, and thus ERK5 over-expression may have implications
in carcinogenesis. High levels of ERK5 are associated with poor patient
prognosis and the presence of bony metastases in advanced prostate
cancer. It has recently been discovered that ERK5 is also involved in
the development and progression of hepatocellular carcinoma (HCC).
Therefore, the discovery and development of small molecule inhibitors of
ERK5 is a desirable therapeutic area.
Method: Two potent inhibitors (1 and 2) have been described in the
literature and provide insight into the therapeutic effect caused by ERK5
inhibition and further guide our structure activity relationship (SAR) studies.
High throughput screening (HTS) of chemical libraries conducted by Cancer
Research Technology identified a number of hit compounds showing ERK5
inhibitory activity.
Results: Benzo[d]thiazole (3) and 3-cyanopyridine (4) based inhibitors
were identified and chosen for validation by re-synthesis. Interestingly, the
compounds showed good to moderate activity against ERK5.
Conclusion: ERK5 inhibition was achieved by two different chemotypes.
The syntheses of these small libraries and their biological evaluation will
be discussed.