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

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.