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  3. Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach

Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach

  • J Am Chem Soc. 2023 Apr 12;145(14):7879-7887. doi: 10.1021/jacs.2c12824.
Fenfang Yang 1,  Qinhong Luo 1 2,  Yuechen Wang 1,  Huiting Liang 2 3,  Yaqi Wang 1,  Zhanfeng Hou 1 3,  Chuan Wan 1,  Yuena Wang 1 4,  Zhihong Liu 3,  Yuxin Ye 3,  Lizhi Zhu 1 2,  Jianlong Wu 2,  Feng Yin 1 3,  Zigang Li 1 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 2 Department of Pharmacy, Department of Gastrointestinal Surgery, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen 518060, China.
  • 3 Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518118, China.
  • 4 Shenzhen Bay Laboratory, Shenzhen 518118, China.
PMID: 37001133 DOI: 10.1021/jacs.2c12824
Abstract

The development of bifunction al molecules, which can enable targeted RNA degradation, targeted protein acetylation, or targeted protein degradation, remains a time-consuming process that requires tedious optimization. We propose a split-and-mix nanoplatform that serves as a self-adjustable platform capable of facile screening, programmable ligand ratios, self-optimized biomolecule spatial recognition, and multifunctional applications. Herein, we demonstrate the potential of our proposed nanoplatform by showcasing proteolysis-targeting chimeras (PROTACs), namely, split-and-mix PROTAC (SM-PROTAC). We highlight the scope of our platform through the targeted disruption of intracellular therapeutic targets involving ERα, CDK4/6, AR, MEK1/2, BRD2/4, Bcr-Abl, etc. These studies confirm the effectiveness and universality of the SM-PROTAC platform for proximity-induced applications. This platform is programmable, with significant potential applications to biomolecule regulation, including the fields of Epigenetics, gene editing, and biomolecule modification regulation.

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