2. Academic Validation
  3. First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein-Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation

First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein-Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation

  • J Med Chem. 2022 Aug 11;65(15):10554-10566. doi: 10.1021/acs.jmedchem.2c00725.
Jonathan E Sandoval 1 2,  Raghav Ramabadran 3 4 5,  Nathaniel Stillson 1,  Letitia Sarah 6,  Danica Galonić Fujimori 6,  Margaret A Goodell 3 4,  Norbert Reich 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States.
  • 2 Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California 93106-9510, United States.
  • 3 Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 5 Interdepartmental Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 6 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, United States.
PMID: 35866897 DOI: 10.1021/acs.jmedchem.2c00725
Abstract

We previously identified two structurally related pyrazolone (compound 1) and pyridazine (compound 2) allosteric inhibitors of DNMT3A through screening of a small chemical library. Here, we show that these compounds bind and disrupt protein-protein interactions (PPIs) at the DNMT3A tetramer interface. This disruption is observed with distinct partner proteins and occurs even when the complexes are acting on DNA, which better reflects the cellular context. Compound 2 induces differentiation of distinct myeloid leukemia cell lines including cells with mutated DNMT3A R882. To date, small molecules targeting DNMT3A are limited to competitive inhibitors of AdoMet or DNA and display extreme toxicity. Our work is the first to identify small molecules with a mechanism of inhibition involving the disruption of PPIs with DNMT3A. Ongoing optimization of compounds 1 and 2 provides a promising basis to induce myeloid differentiation and treatment of diseases that display aberrant PPIs with DNMT3A, such as acute myeloid leukemia.

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