2. Academic Validation
  3. Quinoline-based compounds can inhibit diverse enzymes that act on DNA

Quinoline-based compounds can inhibit diverse enzymes that act on DNA

  • Cell Chem Biol. 2024 Dec 19;31(12):2112-2127.e6. doi: 10.1016/j.chembiol.2024.09.007.
Jujun Zhou 1,  Qin Chen 1,  Ren Ren 1,  Jie Yang 1,  Bigang Liu 1,  John R Horton 1,  Caleb Chang 2,  Chuxuan Li 2,  Leora Maksoud 2,  Yifei Yang 2,  Dante Rotili 3,  Abhinav K Jain 1,  Xing Zhang 1,  Robert M Blumenthal 4,  Taiping Chen 1,  Yang Gao 2,  Sergio Valente 3,  Antonello Mai 5,  Xiaodong Cheng 6
Affiliations

Affiliations

  • 1 Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2 Department of Biosciences, Rice University, Houston, TX 77005, USA.
  • 3 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 4 Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.
  • 5 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 6 Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: xcheng5@mdanderson.org.
PMID: 39437789 DOI: 10.1016/j.chembiol.2024.09.007
Abstract

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (9) or methylpiperazine (11), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and Clostridioides difficile CamA. These compounds (9 and 11) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation. Additionally, some quinoline-based analogs inhibit Other DNA-interacting Enzymes, such as polymerases and base excision repair glycosylases. Finally, compound 11 elicits DNA damage response via p53 activation in Cancer cells.

Keywords

BER glycosylases; DNA adeinine methyltransferases; DNA cytosine methyltransferases; DNA hypomethylating agents; DNA intercalation; DNA/RNA polymerases; non-nucleoside compound; p53 response; pan inhibitors of DNA-acting enzymes; quinoline-based analogs.

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