2. Academic Validation
  3. Discovery of CN0 as a novel proteolysis-targeting chimera (PROTAC) degrader of PARP1 that can activate the cGAS/STING immunity pathway combined with daunorubicin

Discovery of CN0 as a novel proteolysis-targeting chimera (PROTAC) degrader of PARP1 that can activate the cGAS/STING immunity pathway combined with daunorubicin

  • Bioorg Med Chem. 2022 Sep 15:70:116912. doi: 10.1016/j.bmc.2022.116912.
Shanshan Lin 1,  Guihui Tu 2,  Zelei Yu 2,  Qingna Jiang 2,  Lingyu Zhang 3,  Jingwen Liu 2,  Quanyu Liu 2,  Xiuwang Huang 4,  Jianhua Xu 2,  Youwen Lin 5,  Yang Liu 6,  Lixian Wu 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China.
  • 2 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China.
  • 3 Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou 350001, PR China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350001, PR China.
  • 4 Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China; Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China. Electronic address: linhumor@fjmu.edu.cn.
  • 6 Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China; Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China. Electronic address: liuyang@fjmu.edu.cn.
  • 7 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China. Electronic address: wlx-lisa@126.com.
PMID: 35830778 DOI: 10.1016/j.bmc.2022.116912
Abstract

Poly ADP-ribose polymerase 1 (PARP1) plays an essential role in DNA repair signaling, rendering it an attractive target for Cancer treatment. Despite the success of PARP1 inhibitors (PARPis), only a few patients can currently benefit from PARPis. Moreover, drug resistance to PARPis occurs during clinical treatment. Natural and acquired resistance to PARPis has forced us to seek new therapeutic approaches that target PARP1. Here, we synthesized a series of compounds by proteolysis-targeting chimera (PROTAC) technology to directly degrade the PARP1 protein. We found that CN0 (compound 3) with no polyethylene glycol (PEG) linker can degrade the PARP1 protein through the Proteasome pathway. More importantly, CN0 could inhibit DNA damage repair, resulting in highly efficient accumulation of cytosolic DNA fragments due to unresolved unrepaired DNA lesions when combined with daunorubicin (DNR). Therefore, CN0 can activate the Cyclic GMP-AMP Synthase/stimulator of the interferon gene (cGAS/STING) pathway of innate immunity and then spread the resulting inflammatory signals, thereby reshaping the tumor microenvironment, which may eventually enhance T cell killing of tumor cells.

Keywords

DNA repair; Daunorubicin; PARP1; PROTAC; STING.

Figures
Products