Discovery of a selective and effective CRBN-recruiting ATR degrader with strong antitumor activity.

PROTAC has emerged as a promising strategy in the field of drug discovery, offering several advantages such as high target selectivity and the potential to overcome drug resistance et al. However, there have been few reports on ATR-PROTACs to date. In this study, we developed a series of novel ATR-PROTAC molecules, among which compound I-1 demonstrated effective and selective degradation of ATR in ATM-deficient LoVo cells, with DC50 and Dmax values of 6.18 μM and 71.42%, respectively. Preliminary in vitro mechanistic studies revealed that compound I-1 can downregulate the expression of ATR protein, which leads to nuclear envelope breakdown, resulting in genome instability and extensive DNA damage, ultimately triggering cell apoptosis. In addition, I-1 had acceptable pharmacokinetic properties and exhibited significant anti-tumor activity in the LoVo xenograft tumor mouse model. Collectively, these findings suggest that ATR degraders may represent a promising strategy for the treatment of cancer with deficient in ATM.