Discovery of a Potent, Selective, and In Vivo Efficacious Covalent Inhibitor for Lysine Methyltransferase SETD8

Dysregulated signaling of SET domain-containing protein
8 (SETD8)
has been implicated in tumorigenesis, yet most SETD8 inhibitors exhibited
limited cellular efficacy. Herein, we developed a potent and selective
SETD8 covalent inhibitor, MS2928 (3), featuring a propiolamide
covalent warhead. Compound 3 potently and selectively
inhibited SETD8 methyltransferase activity. The covalent inhibition
mechanism of 3 was confirmed by mass spectrometry and
X-ray crystallography. Moreover, 3 significantly reduced
the histone H4 lysine 20 monomethylation (H4K20me1) levels in cells
and robustly inhibited the proliferation of SETD8-overexpressing multiple
myeloma (MM) cell lines with no significant antiproliferative effect
on SETD8-low expressing MM cells and normal cells. Importantly, 3 effectively inhibited tumor growth in vivo in two xenograft mouse models of SETD8-overexpressing MM cell lines.
Collectively, our results establish 3 as a valuable chemical
tool for exploring the biological functions of SETD8 and pave the
way for further development of novel epigenetic therapies for MM.