白血病患者の治療において、より安全で標的を絞った治療を可能にする新しいクラスの薬剤を発見 Researchers identify a new class of drugs that offer a safer, more targeted treatment for leukemia patients
2022-08-24 カリフォルニア大学サンタバーバラ校(UCSB)
これまでに研究された1,500種類の薬剤を含む化学ライブラリーを入手し、DNMT3Aとパートナータンパク質との相互作用を阻害する薬剤(タンパク質-タンパク質阻害剤、PPI)2種類を特定した。
さらに、この2つの薬剤はタンパク質の活性部位に結合しないため、体内の他のすべての細胞で働く酵素DNMT1には影響を与えない。
<関連情報>
- https://www.news.ucsb.edu/2022/020698/new-kind-chemo
- https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00725
ファーストインクラスのDNMT3Aアロステリック阻害剤がタンパク質間相互作用を阻害し、急性骨髄性白血病細胞の分化を誘導することを発見 First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein–Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation
Jonathan E. Sandoval, Raghav Ramabadran, Nathaniel Stillson, Letitia Sarah, Danica Galonić Fujimori, Margaret A. Goodell, and Norbert Reich
Journal of Medicinal Chemistry Published:July 22, 2022
DOI:https://doi.org/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.
