2. Academic Validation
  3. Current advances and development strategies of orally bioavailable PROTACs

Current advances and development strategies of orally bioavailable PROTACs

  • Eur J Med Chem. 2023 Dec 5:261:115793. doi: 10.1016/j.ejmech.2023.115793.
Shenxin Zeng 1,  Yingqiao Ye 2,  Heye Xia 2,  Jingli Min 2,  Jiamei Xu 2,  Zunyuan Wang 2,  Youlu Pan 2,  Xinglu Zhou 3,  Wenhai Huang 4
Affiliations

Affiliations

  • 1 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, China. Electronic address: zengsx@hmc.edu.cn.
  • 2 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, China.
  • 3 HealZen Therapeutics Co., Ltd., Hangzhou, Zhejiang, 310018, China. Electronic address: zhouxl@healzentx.com.
  • 4 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, China. Electronic address: hwh@hmc.edu.cn.
PMID: 37708797 DOI: 10.1016/j.ejmech.2023.115793
Abstract

Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.

Keywords

Bioavailability; Oral PROTACs; Oral pharmacokinetics; Physicochemical properties; bRo5.

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