2. Academic Validation
  3. Discovery of a Potent, Selective, and In Vivo Efficacious Covalent Inhibitor for Lysine Methyltransferase SETD8

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

  • J Med Chem. 2026 Feb 26;69(4):4255-4269. doi: 10.1021/acs.jmedchem.5c02958.
He Chen 1,  Rudra Prasad Dutta 2,  Zhizhong Li 3,  Yue Zhong 1,  Anqi Ma 1,  Kwang-Su Park 1,  Jithesh Kottur 1,  Alison Park 2,  Nicolas Babault 1,  Ke Wang 3,  Dandan Wang 3,  Yan Xiong 1,  H Ümit Kaniskan 1,  Minkui Luo 3 4,  Samir Parekh 2,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2 Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, The Precision Immunology Institute at Mount Sinai, New York, New York 10029, United States.
  • 3 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 4 Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, New York 10021, United States.
PMID: 41693203 DOI: 10.1021/acs.jmedchem.5c02958
Abstract

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.

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