Meisoindigo Acts as a Molecular Glue to Target PKMYT1 for Degradation in Chronic Myeloid Leukemia Therapy.

ABSTRACT: Meisoindigo (Mei) has been clinically utilized for the treatment of chronic myeloid leukemia (CML), yet the precise molecular targets by which it exerts effects remain unclear. Through activity-based protein profiling (ABPP), the protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1) is identified as a direct target of Mei. Specifically, Mei forms a selective and reversible covalent bond with the Cys301 residue of PKMYT1, triggering its K48-linked polyubiquitination and accelerating proteasomal degradation, which is mediated by the E3 ligase TRIM25. The study reveals that Mei acts as a molecular glue, enhancing the interaction between PKMYT1 and TRIM25 by approximately 30-fold, thereby facilitating efficient PKMYT1 degradation. Further investigations reveal the pivotal role of P

SUBMITTER: Zhang ZX 

PROVIDER: S-EPMC12140364 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature