Features and properties of valemetostat

Alternative names	DS-3201; DS-3201b; EZHARMIA; valemetostat tosylate; valemetostat tosilate; (R)‐OR‐S2
Class	Amides; amines; antineoplastics; benzodioxoles; chlorinated hydrocarbons; cyclohexanes; pyridones; small molecules
Mechanism of action	Enhancer of zeste homolog 1 protein inhibitors; enhancer of zeste homolog 2 protein inhibitors
Route of administration	Oral
Pharmacodynamics	Inhibits methylation activity of EZH1/2 [IC50 10.0 nM (EZH1) and 6.0 nM (EZH2), suppressing tri-methylation of H3K27; antiproliferative effects in haematological cancer cell lines [including various NHL cells (GI50 < 100 nM)], regardless of EZH2 mutation status; significantly reduces global H3K27me3 levels and reactivates silenced gene expression; antiproliferative activity against the TL-Om1 cell line derived from human ATL, and the ABC and GCB subtypes of DLBCL cells; induces apoptosis in DLBCL cell lines, regardless of subtype; blocks primary ATL cell survival in vitro and reduces ATL and DLBCL tumour growth in vivo; synergism with NHL and DLBCL standard-of-care treatments in vitro and in vivo
Pharmacokinetics (total valemetostat at steady state; mean values unless stated)	Cmax 2300 ng/mL, median Tmax 3.79 h, AUC24 20,800 ng·h/mL, accumulation ratio 1.19, 94–95% protein bound, Vz/F 68 L, CL/F 58.1 L/h, t½ 11.1 h. Predominantly metabolized by CYP3A; mainly excreted in faeces
Adverse events
Most frequent	Thrombocytopenia, anaemia, alopecia, dysgeusia, lymphopenia, neutropenia, leukopenia
Of special interest	Thrombocytopenia
ATC codes
WHO ATC code	L01 (antineoplastic agents)
EphMRA ATC code	L1 (antineoplastics)
Chemical name	(2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide mono(4- methylbenzenesulfonate)