Summary
MAPKAPK2 (MK2) is a serine/threonine protein kinase activated by the p38 MAP kinase signaling pathway in response to cellular stress and inflammatory cytokines. In cancer, MK2 is implicated in tumor progression, metastasis, and resistance to chemotherapy. Its role in controlling cell survival under stress conditions and modulating the tumor microenvironment makes MK2 a potential target for cancer therapy. While covalent MK2 inhibitors have undergone clinical testing for inflammatory and autoimmune diseases, were they showed good safety but limited efficacy, their application for cancer treatment remains underexplored.
Following up on the strong therapeutic effects of ultralong target residence time p38α inhibitors (ULTR-p38i) in advanced colorectal cancer and other solid tumors (see Ultra-long target residence time p38α inhibitors), we are now investigating MK2 as a novel target for cancer therapy. Building on the Gehringer group’s expertise in covalent inhibitor development, we are exploring different covalent handles to generate highly efficacious MK2 inhibitors with an improved property profile. Our current key compounds show promising results in various cellular and organoid models providing a strong basis for further development. Due to a higher potency and faster inactivation kinetics, these compounds strongly outperform earlier developed covalent MK2 inhibitors such as Gamcemetinib (CC-99677), which was already tested in clinical trials for inflammatory and autoimmune diseases. Within TüCAD2, we are now joining forces to harness our complementary expertise in covalent inhibitor design, synthesis and biochemical evaluation (Gehringer) and cancer biology, advanced organoid and in vivo models (Dauch) for the development of next generation covalent MK2 inhibitors with the ultimate aim of entering clinical evaluation.
