Abstract:

<p>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 (), featuring a propiolamide covalent warhead. Compound potently and selectively inhibited SETD8 methyltransferase activity. The covalent inhibition mechanism of was confirmed by mass spectrometry and X-ray crystallography. Moreover, 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, effectively inhibited tumor growth in two xenograft mouse models of SETD8-overexpressing MM cell lines. Collectively, our results establish 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.</p>