2. Academic Validation
  3. Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1

Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1

  • Acta Pharm Sin B. 2020 Oct;10(10):1943-1953. doi: 10.1016/j.apsb.2020.02.010.
Mingxing Hu 1,  Weilin Zhou 1,  Yijie Wang 1,  Dongping Yao 1,  Tinghong Ye 1,  Yuqin Yao 1,  Bin Chen 1,  Gongping Liu 2 3,  Xifei Yang 4,  Wei Wang 1,  Yongmei Xie 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 2 Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 Innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China.
  • 4 Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Centre for Disease Control and Prevention, Shenzhen 518055, China.
PMID: 33163345 DOI: 10.1016/j.apsb.2020.02.010
Abstract

Cancer Immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers. Indoleamine 2,3-dioxygenase 1 (IDO1), an immune checkpoint, plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for Cancer Immunotherapy. Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a new model for drug research and development for its advantageous mechanism. Herein, we reported the application of PROTAC technology in targeted degradation of IDO1, leading to the discovery of the first IDO1 PROTAC degrader 2c, which induced significant and persistent degradation of IDO1 with maximum degradation (d max) of 93% in HeLa cells. Western-blot based mechanistic studies indicated that IDO1 was degraded by 2c through the ubiquitin Proteasome system (UPS). Label-free real-time Cell Analysis (RTCA) indicated that 2c moderately improved tumor-killing activity of chimeric antigen receptor-modified T (CAR-T) cells. Collectively, these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.

Keywords

IDO1; PROTAC; Protein degradation; Tumor immune escape; Ubiquitin proteasome system.

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