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
  • 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: [email protected].
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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