2. Academic Validation
  3. Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation

Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation

  • J Med Chem. 2024 Jun 27;67(12):9842-9856. doi: 10.1021/acs.jmedchem.3c02340.
Shirui Wang 1,  Zhanzhan Feng 1,  Can Qu 2,  Su Yu 1,  Hongjia Zhang 1,  Rui Deng 1,  Dan Luo 3,  Chunlan Pu 4,  Yan Zhang 5 6,  Rui Li 1
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 3 Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610031, China.
  • 4 Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China.
  • 5 Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 6 Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
PMID: 38839424 DOI: 10.1021/acs.jmedchem.3c02340
Abstract

Advancements in Anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted Cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.

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