2. Academic Validation
  3. A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A

A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A

  • Bioorg Med Chem Lett. 2021 May 15;40:127908. doi: 10.1016/j.bmcl.2021.127908.
Sunzeyu Huang 1,  Nathaniel J Stillson 1,  Jonathan E Sandoval 2,  Chitoh Yung 1,  Norbert O Reich 3
Affiliations

Affiliations

  • 1 The Department of Chemistry and Biochemistry, University of California, Santa Barbara 93106-9510, USA.
  • 2 The Department of Chemistry and Biochemistry, University of California, Santa Barbara 93106-9510, USA; Molecular, Cellular and Developmental Biology, University of California, Santa Barbara 93106-9510, USA.
  • 3 The Department of Chemistry and Biochemistry, University of California, Santa Barbara 93106-9510, USA. Electronic address: [email protected].
PMID: 33705897 DOI: 10.1016/j.bmcl.2021.127908
Abstract

Screening of a small chemical library (Medicines for Malaria Venture Pathogen Box) identified two structurally related pyrazolone (inhibitor 1) and pyridazine (inhibitor 2) DNMT3A inhibitors with low micromolar inhibition constants. The uncompetitive and mixed type inhibition patterns with DNA and AdoMet suggest these molecules act through an allosteric mechanism, and thus are unlikely to bind to the enzyme's active site. Unlike the clinically used mechanism based DNMT inhibitors such as decitabine or azacitidine that act via the Enzyme active site, the inhibitors described here could lead to the development of more selective drugs. Both inhibitors show promising selectivity for DNMT3A in comparison to DNMT1 and Bacterial DNA cytosine methyltransferases. With further study, this could form the basis of preferential targeting of de novo DNA methylation over maintenance DNA methylation.

Keywords

Acute myeloid leukemia target; DNMT1 inhibitors; DNMT3A inhibitors; Non-nucleoside DNA methyltransferase inhibitors.

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