Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells.

ABSTRACT: Mammalian cells replicate ~ 3 × 10⁹ base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia-telangiectasia-and-RAD3-related (ATR). Proteolysis-targeting-chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non-catalytic functions of enzymes. This work defines the first-in-class ATR PROTAC, Abd110/Ramotac-1. It is derived from the ATR inhibitor VE-821 and recruits the E3 ubiquitin-ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti-leukemic effects of the cl

SUBMITTER: Kansy AG 

PROVIDER: S-EPMC11306515 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature