Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer.

ABSTRACT: Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1L^R231Q inhibition through antiproliferation assay and Western blot analysis in the H460^R231Q cell. The most promising compound 37 significantly reduced DOT1L^R231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460^{R231Q OE} cell-derived xenograft (CDX) model, 37 displayed pronounced tumor

SUBMITTER: Tan Z 

PROVIDER: S-EPMC11365375 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature