Table 2.

Comprehensive list of small-molecule inhibitors of m6A writers and erasers, detailing their mechanisms, preclinical findings, and clinical stage

Drug name	Target protein	Binding mode and mechanism	Key biological findings	Preclinical Cell Models	Development stage/Clinical Trial ID	References
STM2457	METTL3	SAM-binding pocket antagonist; inhibits METTL3–METTL14 heterodimer	Impairs AML expansion; transient, reversible hematopoietic lineage bias (myeloid increased via interferon response; erythroid decreased with anemia; thrombocytosis); HSCs spared; favorable tolerability; fully reversible upon cessation	AML (PDX models); HepG2 hepatocytes	Preclinical; leads to STC-15 (NCTO5584111)	[165–169]
STM2120	METTL3	SAM-binding site antagonist; SAM-competitive (less potent variant)	Less active than STM2457; reference compound; no effect on normal hematopoietic proliferation/differentiation in vitro; does not impair AML cells	Human AML cell lines; Normal bone marrow cells	Preclinical	[165]
UZH1a	METTL3	SAM-competitive; structure-based design with increased selectivity	Decreased m6A levels; decreased GSC proliferation; increased apoptosis and cell cycle arrest in AML cells	Glioblastoma stem cells (GSCs); AML cell lines; Mouse xenograft models	Preclinical	[170, 172, 173]
UZH2	METTL3	SAM-competitive; enhanced binding vs UZH1a	Anti-cancer potential against AML, prostate cancer, GBM; decreased proliferation; increased cell death	AML cell lines; Prostate cancer cell lines; Glioblastoma stem cells; Mouse xenograft models	Preclinical	[170, 174]
STC-15 (STM3480)	METTL3	METTL3 catalytic domain antagonist; optimized for oral bioavailability	First METTL3 inhibitor in clinical trials (Phase 1, NCT05584111). Favorable tolerability profile; no dose-limiting toxicities at tested doses. Identical mechanism to STM2457; clinical monitoring of hematopoietic effects ongoing on	Phase 1 Clinical: Advanced solid tumors Preclinical: AML models	Phase 1 Clinical/NCTO5584111	[171, 175]
STM3006	METTL3	METTL3 catalytic domain-selective antagonist	Enhanced specificity; designed for reduced off-target effects; improved selectivity over STM2457	AML cell lines; In vitro and in vivo models (optimization ongoing)	Preclinical	[171]
FB23 (compound 16a)	FTO	L-shaped MA-pocket binding; Ser229 H-bond; Arg96 contact; 140-fold improvement over MA inhibitor	Decreased AML proliferation; increased m6A abundance; direct target engagement; potent structural precursor	AML models (in vivo studies)	Preclinical (in vivo)	[177]
FB23-2 (compound 16b)	FTO	L-shaped MA-pocket binding; improved penetration; intramolecular H-bond vs FB23	Increased m6A abundance; decreased AML proliferation; selective p53/apoptosis upregulation; minimal effects on normal bone marrow cells	AML cell lines (HL60, MV4-11); Normal bone marrow (from healthy donors); Mouse xenografts	Preclinical (in vivo)	[177]
Dac51	FTO	Selective FTO antagonist; blocks m6A demethylation on immune genes	5-fold potency vs FB23-2; T-ALL-specific: suppresses glycolytic gene expression; profound lethal effects on T-ALL cell lines; minimal toxicity to normal bone marrow; minimal body weight changes; tolerable systemic toxicity	T-ALL cell lines (KOPTK1, CUTLL1, etc.); Normal bone marrow cells (from healthy donors); Mouse xenograft models (T-ALL)	Preclinical (in vivo validated)	[178]
IOX1	ALKBH5 (limited FTO selectivity)	2-oxoglutarate analog; chelates Fe2 +/Mn2 + in AlkB domain; selective ALKBH5 inhibition with FTO cross-reactivity at higher concentrations	Alleviates renal IRI; modulates epitranscriptomic regulation through m6A accumulation; enhanced cell protection against ferroptosis in normal renal cells; preserved antioxidant pathways (GSH, GPX4)	Renal tubular epithelial cells (HK-2); C57BL/6J mice (renal IRI model); Normal kidney tissue showed selectivity	Preclinical	[179, 180]
MV1035	ALKBH5	Optimized for ALKBH5 restricted cavity; dual-target ALKBH5 + ALKBH2	Decreased GBM migration/invasiveness; increased m6A methylation; overcomes temozolomide (TMZ) resistance; synergizes with TMZ in patient-derived GSCs; partial monotherapy effect; synergistic combo activity	Glioblastoma stem cells (patient-derived lines); U87 GBM cells; HK-2 renal cells	Preclinical (in vitro validated; in vivo ongoing)	[181]
DDO-2728	ALKBH5	Selective ALKBH5 inhibitor; pyrazolo[1,5-a] pyrimidine scaffold	Paradigmatic example of context-dependency: • AML: Suppresses tumor growth via TACC3-dependent proliferation • Myopia: Attenuates progression; suppresses inflammatory mediators; modulates ECM dysregulation through ERK1/2 suppression • AKI: Suppresses ferroptosis; improves renal function • All contexts: Protective in normal tissues without overt toxicity	AML: MV4-11 xenografts Myopia: FDM mouse retinal models AKI: Cisplatin-induced AKI mice + HK-2 cells Normal tissues tested: Renal, retinal	Preclinical (multiple indications)	[180, 182, 183]