MS2928 is a selective SETD8 inhibitor with an IC50 of 0.14 μM against SETD8 methyltransferase activity. MS2928 reduces cellular H4K20 me1 levels and inhibits proliferation of SETD8-overexpressing multiple myeloma cells. MS2928 inhibits tumor growth in xenograft mouse models of SETD8-overexpressing multiple myeloma. MS2928 can be used for the study of SETD8 biological functions and multiple myeloma [1].
In Vivo, MS2928 (compound 3) (25 mg/kg; i.p.; twice daily; 14 days) significantly inhibits JJN-3 multiple myeloma xenograft tumor growth in female NSG mice with no overt toxicity[1]. MS2928 (25 mg/kg; i.p.; twice daily; 16 days) significantly inhibits OPM-2 multiple myeloma xenograft tumor growth in female NSG mice, reduces tumor cell proliferation and SETD8-mediated H4K20 monomethylation, and is well tolerated[1].
In Vitro, MS2928 (compound 3) potently inhibits purified human SETD8 methyltransferase activity with an IC50 of 0.14 μM[1]. MS2928 (20 μM; 1 h) covalently modifies wild-type human SETD8 at the C311 residue, as no covalent adduct forms with the SETD8C311S mutant[1]. MS2928 (1 μM) is a selective inhibitor of SETD8, showing no significant inhibition of 20 other human methyltransferases at 1 μM[1]. MS2928 (2.5-5.0 μM; 12 h) reduces H4K20me1 levels in SETD8-overexpressing JJN-3 and OPM-2 human multiple myeloma cells in a concentration-dependent manner after 12 h of treatment[1]. MS2928 (serial dilutions; 72 h) potently inhibits the viability of SETD8-overexpressing JJN-3 and OPM-2 human multiple myeloma cells after 72 h of treatment, with IC50 values of 1.06 μM and 0.54 μM, respectively[1]. MS2928 (0.1-10 μM; 16-24 h) only reduces H4K20me1 levels at higher concentrations in SETD8-low expressing human multiple myeloma cells (MM.1S, KMS20, EJM) and normal human cells (PBMC, PNT2, MCF10A) after 16-24 h of treatment[1]. MS2928 (0.06-15 μM; 72 h) does not significantly inhibit the viability of SETD8-low expressing human multiple myeloma cells (MM.1S, KMS20, EJM) or normal human cells (PBMC, PNT2, MCF10A) at concentrations up to 15 μM after 72 h of treatment[1].
References:
[1]. Chen H, et al. Discovery of a Potent, Selective, and In Vivo Efficacious Covalent Inhibitor for Lysine Methyltransferase SETD8. J Med Chem. 2026;69(4):4255-4269.
In Vivo, MS2928 (compound 3) (25 mg/kg; i.p.; twice daily; 14 days) significantly inhibits JJN-3 multiple myeloma xenograft tumor growth in female NSG mice with no overt toxicity[1]. MS2928 (25 mg/kg; i.p.; twice daily; 16 days) significantly inhibits OPM-2 multiple myeloma xenograft tumor growth in female NSG mice, reduces tumor cell proliferation and SETD8-mediated H4K20 monomethylation, and is well tolerated[1].
In Vitro, MS2928 (compound 3) potently inhibits purified human SETD8 methyltransferase activity with an IC50 of 0.14 μM[1]. MS2928 (20 μM; 1 h) covalently modifies wild-type human SETD8 at the C311 residue, as no covalent adduct forms with the SETD8C311S mutant[1]. MS2928 (1 μM) is a selective inhibitor of SETD8, showing no significant inhibition of 20 other human methyltransferases at 1 μM[1]. MS2928 (2.5-5.0 μM; 12 h) reduces H4K20me1 levels in SETD8-overexpressing JJN-3 and OPM-2 human multiple myeloma cells in a concentration-dependent manner after 12 h of treatment[1]. MS2928 (serial dilutions; 72 h) potently inhibits the viability of SETD8-overexpressing JJN-3 and OPM-2 human multiple myeloma cells after 72 h of treatment, with IC50 values of 1.06 μM and 0.54 μM, respectively[1]. MS2928 (0.1-10 μM; 16-24 h) only reduces H4K20me1 levels at higher concentrations in SETD8-low expressing human multiple myeloma cells (MM.1S, KMS20, EJM) and normal human cells (PBMC, PNT2, MCF10A) after 16-24 h of treatment[1]. MS2928 (0.06-15 μM; 72 h) does not significantly inhibit the viability of SETD8-low expressing human multiple myeloma cells (MM.1S, KMS20, EJM) or normal human cells (PBMC, PNT2, MCF10A) at concentrations up to 15 μM after 72 h of treatment[1].
References:
[1]. Chen H, et al. Discovery of a Potent, Selective, and In Vivo Efficacious Covalent Inhibitor for Lysine Methyltransferase SETD8. J Med Chem. 2026;69(4):4255-4269.