2. Academic Validation
  3. Design, synthesis of auristatins-glucuronide conjugates targeting the β-glucuronidase in tumor microenvironment

Design, synthesis of auristatins-glucuronide conjugates targeting the β-glucuronidase in tumor microenvironment

  • Bioorg Med Chem Lett. 2023 Oct 15:95:129493. doi: 10.1016/j.bmcl.2023.129493.
Yujie Wang 1,  Keshi Xu 2,  Hongchun Liu 3,  Wei Zhang 2,  Chun Hu 4,  Yingxia Li 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2 Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education of China, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education of China, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: chunhu@syphu.edu.cn.
  • 5 School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.
PMID: 37793497 DOI: 10.1016/j.bmcl.2023.129493
Abstract

Auristatins-glucuronide conjugates designed targeting the β-Glucuronidase in tumor microenvironment were synthesized and evaluated on stabilities, the release of auristatins and the antitumor activities in this study. Conjugates 20 and 21 showed remarkable stabilities in phosphate buffer and bovine serum solution, and excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase pretreated and untreated Cancer cells (IC50 = 5.7 nM ∼ 9.7 nM, IC50 (-Enz) > 1 μM). Furthermore, conjugate 20 showed potent antitumor efficacy in HCT-116 xenograft mouse model without inducing side effects.

Keywords

Antiproliferation; Auristatin E; Tumor microenvironment; β-Glucuronidase.

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