Identification of XZ8078 as a Dual-Target Degrader Targeting PARP1 and IKZF3 for Broad Spectrum Anticancer Treatment
- J Med Chem. 2026 Jul 23;69(14):16629-16657. doi: 10.1021/acs.jmedchem.6c00239.
- 1. Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China.
- 2. State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
- 3. University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
- 4. Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
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.