Table 2.

Epigenetic inhibitors targeting synthetic lethal relationships in clinical development.

Epigenetic alteration	Target	Inhibitor	Indication	Rationale	Clinical trial number
ARID1A mutation/LOF	EZH2	Tazemetostat	Ovarian cancer	epigenetic antagonism between SWI/SNF and PcG (Polycomb group protein) [118]	NCT05023655, NCT03348631
BAP1 loss	EZH2	Tazemetostat	Mesothelioma	decrease in H4K20 monomethylation, increase in EZH2 expression [119]	NCT02860286
SMARCA4 mutation/LOF	SMARCA2	PRT-3789 PRT-7732 FHD-909 LY4050784	Solid tumors	paralog dependency in SWI/SNF [106,107]	NCT05639751 NCT06560645 NCT06561685
SYT-SSX	EZH2	Tazemetostat	Synovial sarcoma	epigenetic antagonism between PcG and SWI/SNF [120]	NCT02601937, NCT02601950
SMARCB1	EZH2	Tazemetostat	malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (ATRT)	epigenetic antagonism between PcG and SWI/SNF [97,121]	NCT03213665, NCT02601950
SMARCB1	HDAC	Vorinostat	MRT and ATRT	restore histone acetylation in SMARCB1-null cells [122]	NCT04897880
CREBBP mutation/LOF	p300	CCS-1477	Lung cancer, Heme cancer	paralog dependency [117]	NCT04068597
MTAP	PRMT5	AMG-193, TNG-908, MRTX-1719 TNG-462 AZD-3470	Multiple cancers	preferential PRMT5 inhibition by MTA in MTAP deleted cancer [101,102,123]	NCT05245500, NCT05094336, NCT05275478, NCT05732831 NCT06130553 NCT06137144