ERK is the effector
kinase of the RAS-RAF-
MEK-ERK signaling cascade, which promotes cell transformation and
malignancy in many
cancers and is thus a major drug target in oncology.
Kinase inhibitors targeting RAF or
MEK are already used for the treatment of certain
cancers, such as
melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination
therapies targeting both RAF and
MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector
kinase ERK, making it a promising target for drug development efforts. Here, we report the design and structural/functional characterization of a set of bivalent ERK inhibitors that combine a small molecule inhibitor that binds to the
ATP-binding pocket with a
peptide that selectively binds to an ERK
protein interaction surface, the D-site recruitment site (DRS). Our studies show that the lead bivalent inhibitor, SBP3, has markedly improved potency compared to the small molecule inhibitor alone. Unexpectedly, we found that SBP3 also binds to several ERK-related
kinases that contain a DRS, highlighting the importance of experimentally verifying the predicted specificity of bivalent inhibitors. However, SBP3 does not target any other
kinases belonging to the same CMGC branch of the kinome. Additionally, our modular click chemistry inhibitor design facilitates the generation of different combinations of small molecule inhibitors with ERK-targeting
peptides.