Table 2 SETD8 inhibitors

H acid

IC₅₀ = 3.8 μM also inhibits EZH2 (3.0 μM); no inhibition of G9a, SETD7 and PRMT1

Not cell permeable

[79]

Thymolphthalein

IC₅₀ = 9.0 μM also inhibits EZH2 (25.2 μM); no inhibition of G9a, SETD7 and PRMT1

Marked concentration-dependent effect on HeLa cells viability; evident reduction of H4K20me1; does not affect other histone methylation marks; possible interference with the binding to the nucleosome

[79]

EBI-099

IC₅₀ = 4.7 μM no inhibition of G9a

Antiproliferative effects against human myelogenous leukemia K562 cells

[83]

MC1946

MC1948

IC₅₀ = 3.3 μM and 2.6 μM, respectively; no inhibition of EZH2, G9a and SETD7

Both compounds (50 μM) reduce H4K20me1 in U937 cells; possible covalent inhibiton

[86]

MC1947

MC2569

Dual inhibitors of SETD8 (IC₅₀ = 9.0 μM and 10.2 μM, respectively) and EZH2 (IC₅₀ = 74.9 μM and 313.8 μM, respectively); no inhibition of G9a and SETD7

Both compounds (50 μM) reduce H4K20me1 in U937 cells; MC1947 induces massive cell death and increases granulocytic differentiation; possible covalent inhibition

[86]

Nahuoic acid A

IC₅₀ = 6.5 μM no inhibition of G9a, EHMT1, SETD7, SUV39H2, SUV420H1, SUV420H2, DOT1L, PRMT3, PRMT5 and MLL complexes

SAM-competitive and substrate-noncompetitive; the compound inhibits SETD8 in U2OS osteosarcoma cells

[87, 88]

UNC0379

IC₅₀ = 7.3 μM no inhibition of G9a, SETDB1, GLP, SUV39H2, SETD7, PRMT3, PRMT5-MEP50 complex, PRMT1, SUV420H1, SUV420H2, SMYD2, DNMT1, PRC2 complex, MLL1 complex, and DOT1L

Substrate-competitive and SAM-noncompetitive; no cellular activity reported

[95, 96]

SPS8I1 (NSC663284)

IC₅₀ = 0.21 μM inhibits SETD2, G9a, SMYD2, CARM1, and PRMT3 with IC₅₀ values in the low micromolar or submicromolar range; no inhibition of GLP, SETD7, PRMT1

Substrate-dependent and irreversible inhibitor of SETD8; reduces H4K20me1 in HEK293T cells and produces a cell cycle arrest phenotype; off-target inhibition of Cdc25

[97]

SPS8I2 (Ryuvidine)

IC₅₀ = 0.50 μM inhibits GLP, SETD2, G9a, SMYD2, CARM1, and PRMT3 with IC₅₀ values in the low micromolar or submicromolar range; no inhibition of SETD7, PRMT1

Substrate- and cofactor independent; irreversible inhibitor of SETD8; reduces H4K20me1 in HEK293T cells and produces a cell cycle arrest phenotype; off-target inhibition of cyclin-dependent kinase 4 and 2 (CDK4/2)

[97]

SPS8I3 (BVT948)

IC₅₀ = 0.70 μM inhibits SETD2, G9a, SMYD2, CARM1, and PRMT3 with IC₅₀ values in the low micromolar or submicromolar range; no inhibition ofGLP, SETD7, PRMT1

Substrate- and SAM-dependent; irreversible inhibitor of SETD8; reduces H4K20me1 in HEK293T cells and produces a cell cycle arrest phenotype; off-target inhibition of protein tyrosine phosphatase PTB1B

[97]

SGSS05-N

SGSS05-NS

SPECS21

Inhibit SETD8 with IC₅₀ values ≤ 5 μM also inhibit SETD2, SETDB1, GLP, G9a, SMYD2, SMYD3, MLL1, SETD7, PRMT1, PRMT3, CARM1, PRMT8 in the low micromolar range

[98]