Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the ataxia telangiectasia and RAD3-related (ATR) kinase

  • Eur J Med Chem. 2024 Mar 5:267:116167. doi: 10.1016/j.ejmech.2024.116167.
Abdallah M Alfayomy  1 ,  Ramy Ashry  2 ,  Anita G Kansy  3 ,  Anne-Christin Sarnow  4 ,  Frank Erdmann  4 ,  Matthias Schmidt  4 ,  Oliver H Krämer  5 ,  Wolfgang Sippl  6
Affiliations
  • 1. Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120, Halle (Saale), Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt.
  • 2. Department of Toxicology, University Medical Center, Johannes Gutenberg-University Mainz, 55131, Mainz, Germany; Department of Oral Pathology, Faculty of Dentistry, Mansoura University, Mansoura, 35516, Egypt.
  • 3. Department of Toxicology, University Medical Center, Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
  • 4. Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120, Halle (Saale), Germany.
  • 5. Department of Toxicology, University Medical Center, Johannes Gutenberg-University Mainz, 55131, Mainz, Germany. Electronic address: [email protected].
  • 6. Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120, Halle (Saale), Germany. Electronic address: [email protected].
PMID: 38308949 DOI: 10.1016/j.ejmech.2024.116167
Abstract

The Ataxia telangiectasia and RAD3-related (ATR) kinase is a key regulator of DNA replication stress responses and DNA-damage checkpoints. Several potent and selective ATR inhibitors are reported and four of them are currently in clinical trials in combination with radio- or chemotherapy. Based on the idea of degrading target proteins rather than inhibiting them, we designed, synthesized and biologically characterized a library of ATR-targeted proteolysis targeting chimera (PROTACs). Among the synthesized compounds, the lenalidomide-based PROTAC 42i was the most promising. In pancreatic and cervix Cancer cells Cancer cells, it reduced ATR to 40 % of the levels in untreated cells. 42i selectively degraded ATR through the Proteasome, dependent on the E3 ubiquitin Ligase component Cereblon, and without affecting the associated kinases ATM and DNA-PKcs. 42i may be a promising candidate for further optimization and biological characterization in various Cancer cells.

Keywords
Ataxia telangiectasia and RAD3-Related (ATR) kinase; MIA PaCa-2; Protein degradation; Proteolysis targeting chimera (PROTAC); Synthesis.
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