Identification of XZ8078 as a Dual-Target Degrader Targeting PARP1 and IKZF3 for Broad Spectrum Anticancer Treatment.

Targeted protein degradation represents an emerging new drug discovery strategy. Herein, we identified a novel and potent dual-target degrader targeting PARP1 and IKZF3 based on our previously reported PARPi Thioparib. In vitro, compound C16a (XZ8078) exerted impressive antiproliferative activities against HR-deficient cancer cells with IC50 values ranging from 0.006 nM to 39.41 nM. Concurrently, compound C16a displayed potent cell growth inhibitory activities against HR-proficient and clinically used PARPi-resistant cancer cells, with efficacy significantly superior to that of AZD5305. In vivo, compound C16a demonstrated excellent tumor growth inhibition (TGI) in the AZD5305-sensitive/-insensitive xenograft model with TGI values of 133.6% and 71.9%, respectively. Collectively, compound C16a may be a powerful therapeutic agent not only for treating PARPi-sensitive tumors but also PARPi-resistant tumors, even HR-proficient tumors.