Identification of dual-targeting PROTACs for ataxia telangiectasia and RAD3-related and aurora kinase A as chemo-sensitizers for leukemia cells

  • Eur J Med Chem. 2026 Jul 10:318:119125. doi: 10.1016/j.ejmech.2026.119125.
Abdallah M Alfayomy  1 ,  Sarah Neuroth  2 ,  Anne-Christin Sarnow  3 ,  Lukas Handke  4 ,  Dina Robaa  3 ,  Frank Erdmann  3 ,  Christophe Decroos  5 ,  Matthias Schmidt  3 ,  Chris Romier  5 ,  Mike Schutkowski  4 ,  Oliver H Krämer  6 ,  Wolfgang Sippl  7
Affiliations
  • 1. Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), 06120, Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt.
  • 2. Institute of Toxicology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
  • 3. Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), 06120, Germany.
  • 4. Institute of Biochtechnology and Biochemistry, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), 06120, Germany.
  • 5. Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, Illkirch Cedex, 67404, France.
  • 6. Institute of Toxicology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, 55131, Germany. Electronic address: [email protected].
  • 7. Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), 06120, Germany. Electronic address: [email protected].
PMID: 42462624 DOI: 10.1016/j.ejmech.2026.119125
Abstract

The ataxia telangiectasia and RAD3-related (ATR) kinase is a central regulator of DNA damage responses. Its pharmacological degradation by proteolysis-targeting chimeras (PROTACs) represents a promising strategy to sensitize Cancer cells to DNA-damaging chemotherapy. It is currently unknown if ATR PROTACs can be pharmacologically designed to target a second cancer-relevant kinase. In this study, we report the design, synthesis, and biological evaluation of novel Cereblon (CRBN)-based PROTACs for ATR. Structure-guided design and chemical synthesis enabled the development of a focused library of degraders based on selective ATR inhibitors and optimized CRBN ligands. Among the synthesized compounds, Abd141 turns out as the most promising degrader, showing potent ATR degradation in human leukemia cells, without affecting ATM, Wee1 or DNA-PKcs. Consistently, the developed PROTACs prove activity in an in vitro ATR/ATRIP binding assay. Abd141 exhibits high chemical, microsomal, and plasma stability, and no cytotoxicity in non-cancerous HEK293 cells. Proteomic studies and immunoblot experiments identify Aurora Kinase A (AURKA) as additional target of CRBN-induced proteasomal degradation by Abd141. Dose-degradation studies of Abd141 in the MOLT-4 cell line yielded a DC50 of 97.7 nM for ATR and 6.7 nM for AURKA. These findings disclose Abd141 as effective dual ATR/AURKA degrader and innovative chemo-sensitizer that encourages preclinical development.

Keywords
Ataxia telangiectasia and RAD3-Related (ATR) kinase; Aurora kinase A; Blood cancer cells; Docking study; Proteolysis targeting chimera (PROTAC).
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