Targeted degradation of MK2 is insufficient to block inflammatory cytokine production in human cells due to cooperativity with MK3 and MK5.

ABSTRACT: Multiple p38 MAP kinase inhibitors have been developed for the treatment of inflammatory diseases such as rheumatoid arthritis, but their effectiveness has been limited due to toxicity and tachyphylaxis, leading to a lack of clinical benefit. Efforts have been made to circumvent this limitation by targeting individual substrates downstream of p38, including MK2 and MK5. This approach has failed to yield clinical benefit despite preclinical evidence of a therapeutic effect. We hypothesized that there is redundancy in the MAPK activating kinase family that would necessitate blocking multiple kinases to sufficiently impact inflammatory processes. We used heterobifunctional protein degraders that either specifically degraded MK2 selectively or degraded MK2/3/5 simultaneously to test the hypoth

SUBMITTER: Yang B 

PROVIDER: S-EPMC12847452 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature