2. Academic Validation
  3. Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

  • Proc Natl Acad Sci U S A. 2021 Jun 22;118(25):e2107042118. doi: 10.1073/pnas.2107042118.
K C Nicolaou 1,  Stephan Rigol 2,  Emmanuel N Pitsinos 2 3,  Dipendu Das 2,  Yong Lu 2,  Subhrajit Rout 2,  Alexander W Schammel 4,  Dane Holte 4,  Baiwei Lin 5,  Christine Gu 5,  Hetal Sarvaiya 5,  Jose Trinidad 5,  Nicole Barbour 5,  Amanda M Valdiosera 5,  Joseph Sandoval 6,  Christina Lee 6,  Monette Aujay 6,  Hanan Fernando 7,  Anukriti Dhar 7,  Holger Karsunky 7,  Nicole Taylor 8,  Marybeth Pysz 8,  Julia Gavrilyuk 9
Affiliations

Affiliations

  • 1 BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005; kcn@rice.edu julia.gavrilyuk@gmail.com.
  • 2 BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005.
  • 3 Laboratory of Natural Products Synthesis & Bioorganic Chemistry, Institute of Nanoscience and Nanotechnology, National Centre for Scientific Research "Demokritos", 153 10 Agia Paraskevi, Greece.
  • 4 Discovery Chemistry Department, AbbVie Inc., South San Francisco, CA 94080.
  • 5 Bioconjugation and Process Development Department, AbbVie Inc., South San Francisco, CA 94080.
  • 6 Assay Development Department, AbbVie Inc., South San Francisco, CA 94080.
  • 7 Cancer Biology Department, AbbVie Inc., South San Francisco, CA 94080.
  • 8 In Vivo Pharmacology Department, AbbVie Inc., South San Francisco, CA 94080.
  • 9 Discovery Chemistry Department, AbbVie Inc., South San Francisco, CA 94080; kcn@rice.edu julia.gavrilyuk@gmail.com.
PMID: 34155147 DOI: 10.1073/pnas.2107042118
Abstract

Antibody-drug conjugates (ADCs) have emerged as valuable targeted Anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

Keywords

antibody–drug conjugates; bystander killing effect; enediyne payloads.

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