Table 3.

Molecules targeting RNA m6A regulators and their clinical application

Compound	Target	IC50	Cancer Type	Mechanism	Clinical Trial	Targeted Disease	ClinicalTrials gov ID	Reference
STM2457	METTL3	16.9 μM	AML	STM2457 inhibits the activity of METTL3, thereby reducing the level of intracellular m6A modification, leading to the differentiation and apoptosis of AML cells	no	no	/	[240]
STC-15	METTL3	Unknown	AML	STC-15 has also been shown to inhibit tumor growth through mechanisms involving anti-cancer immune responses such as changes in interferon signaling and synergy with T-cell checkpoint blockade	Phase I	AML	NCT05584111	/
UZH2	METTL3	0.28 μM	AML	UZH2 can enter cells and bind to METTL3 in a targeted manner, thereby inhibiting its enzymatic activity and reducing m6A levels in MOLM-13 and PC-3 tumor cell lines, inhibiting tumor cell proliferation	no	no	/	[241]
CDIBA-43n	METTL3/14	16.9 μM	AML	CDIBA-43n inhibits AML cell proliferation by inhibiting METTL3-14 complex and reducing the level of m6A modification of mRNAs	no	no	/	[242]
Eltrom-Bopag	METLL3/14	3.65 μM	AML	Eltrombopag inhibits AML cell proliferation by inhibiting METTL3 activity and decreasing m6A levels	Phase II Phase III	LymphomaAML	NCT05961410 NCT03701217	[243]
Metformin	METTL3	Unknown	BC	Metformin inhibits breast cancer cell proliferation by targeting the miR-483-3p/METTL3/m6A/p21 pathway	Phase II Phase II Phase II	BC                                                              SCLC, LUAD	NCT01042379 NCT03994744 NCT03709147	[244]
Baicalin	METTL3, METTL14	Unknown	NPC	Baicalin elevated METTL3 and METTL14 levels to augment m6A methylation of Suv39H1 mRNA.Enhanced m6A methylation facilitated diverse Suv39H1 cleavage, influencing genomic stability in cancer cells and yielding anti-tumor effects	no	no	/	[235]
Fusaric acid (FA)	METTL3, METTL14	Unknown	HCC	FA increased hypermethylation of the p53 gene promoter, impeding p53 transcription, and diminished the synthesis of the m6A methyltransferases METTL3 and METTL14, hence decreasing the m6A modification of p53 mRNA and P53 expression	no	no	/	[237]
2-((1-hydroxy-2-oxo-2-phenylethylthio)-acetic acid	ALKBH5	0.84 μM	AML	Compounds 7 and 8 bind with the ALKBH5 protein. At low micromolar levels, there was a notable reduction in cell proliferation and survival	no	no	/	[248]
4-((furan-2-ylmethyl)-amino)	ALKBH5	1.79 μM	AML
DDO-2728	ALKBH5	2.97 μM	AML	Compound 10 interacts with ALKBH5 by occupying the m6A-binding pocket. This interaction leads to the suppression of AML cell growth by influencing the cell cycle, E2F targets, G2M checkpoints, and MYC targets	no	no	/	[249]
ALK-04	ALKBH5	Unknown	Melanoma	The combination of compound 11 (ALK-04) with the PD-1 antibody and GVAX has demonstrated a substantial inhibitory effect on the growth of B16 tumors in melanoma by blocking the function of the ALKBH5 enzyme	no	no	/	[211]
MV1035	ALKBH5	Unknown	GBM	MV1035 competes with 2-oxoglutarate for the binding site of ALKBH5, essential for its catalytic function, hence diminishing CD73 expression and restricting GBM cell invasion and migration	no	no	/	[250]
MO-I-500	FTO	1.51 μM	TNBC	MO-I-500 possesses both anticonvulsant characteristics and the ability to efficiently inhibit the survival and growth of drug-resistant triple-negative breast cancer (TNBC) cells, specifically the SUM149-MA cell line, via blocking FTO	no	no	/	[252]
Diacerein	FTO	8.7 μM	BC	Diacerein could hinder the IL-6/IL-6R signaling route, leading to the down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL, and the up-regulation of the pro-apoptotic protein Bax, so causing death in tumor cells. Additionally, it inhibits the STAT3, MAPK, and Akt signaling pathways, which suppresses tumor cell growth	no	no	/	[253, 254]
18077	FTO	1.43 μM	BC	The administration of 18077 and 18097 resulted in a substantial increase in the quantity of m6A-modified mRNA in cancer cells. This increase improved the stability of SOCS1 mRNA and stimulated the p53 signaling pathway, hence enhancing the cells' sensitivity to chemotherapy such as cisplatin and doxorubicin	no	no	/	[255]
18097	FTO	0.64 μM	BC
Meclofenamic acid	FTO	17.4 μM	NSCLC	Administration of Meclofenamic acid demonstrated a significant synergistic effect in GE-resistant non-small cell lung cancer (NSCLC) cells with the combination of Meclofenamic acid and geftinib (GE)	no	no	/	[256, 257]
ZLD115	FTO	2.3 μM	AML	ZLD115 can upregulate RARA and downregulate MYC levels in MOLM13 cells, inhibiting the oncogenic FTO signaling pathway in AML cells, thereby demonstrating anti-leukemic activity	no	no	/	[259]
FB23	FTO	0.06 μM	AML	FB23-2 triggers apoptosis, and increases the expression of ASB2 and RARA, which are direct targets of FTO, thereby exerting anti-tumor effects	no	no	/	[258]
FB23-2	FTO	1.6-16 μM	AML
Dac51	FTO	0.4 μM	Melanoma, CRC	Dac51 enhances CD8+ T cell infiltration and IFN-γ release in melanoma, hence restricting tumor development. The combination of Dac51 and anti-PD-L1 therapy significantly prolongs the longevity of MC38 colon cancer murine models.	no	no	/	[260]
FTO-02	FTO	2.18 μM	GBM	FTO-04 impedes the development of neutrospheres produced from GSCs, but does not impact the proliferation of neutrospheres produced from normal neural stem cells.	no	no	/	[261]
FTO-04	FTO	3.39 μM
FTO-43N	FTO	1.0 μM	GC	Administration of FTO-43N is associated with the downregulation of the Wnt and PI3K-Akt signaling pathways, while exhibiting no growth toxicity to normal colon cells.	no	no	/	[262]
Zantrene	FTO	Unknown	AML, CRCC	Zantrene has been identified as a potent targeted inhibitor of FTO, and inhibition of FTO via Zantrene administration can overcome PD-1 immune checkpoint resistance in mouse melanoma models.	Phase I	AML, melanoma, and CRCC	NCT05456269	/
Entacapone	FTO	Unknown	Osteos-arcoma (OS)	Elevated FTO levels in OS may signify a worse prognosis. FTO accelerated OS development and metastasis both in vitro and in vivo. Entacapone, a treatment for Parkinson's disease, inhibited oxidative stress via m6A-mediated regulation of FTO and DACT1.	Early Phase I	Gastrointestinal stromal tumors	NCT04006769	/
Saiko-saponin	FTO	Unknown	Leu-kemia	Saikosaponin D stopped FTO and fixed m6A hypomethylation in MYC and RARA. After these effects, MTHFR and BCL2 became less stable, which made MV4-11- or Kas-1-resistant human myeloid mononuclear leukemia cells more sensitive to tyrosine kinase inhibitors.	no	no	/	[246]
CuB	IGF2BP1	1.7 μM	HCC	CuB  has been demonstrated to obstruct the recognition of c-Myc mRNA by IGF2BP1 through allosteric mechanisms. As a result, this results in the activation of apoptosis, the reestablishment of the immunological response, and the manifestation of anti-hepatoma properties.	no	no	/	[264]
Tegaserod	YTHDF1	13.82 μM	AML	Tegaserod  inhibits the YTHDF1-regulated translation of cyclin E2 and blocks the G1 phase of CD34+ cells.	no	no	/	[265]
DC-Y13-27	YTHDF2	21.8±1.8 μM	CRC	DC-Y13-27  can augment anti-PD-L1 treatment in MC38 murine models. Meanwhile, DC-Y13-27  could suppress YTHDF2 expression to counteract IR-induced immunosuppression and enhance adaptive immunity, facilitating IR in combination treatment.	no	no	/	[266]
JX5	IGF2BP2	Unknown	T-ALL	JX5 can inhibit the NOTCH1 signaling pathway by suppressing the binding of IGF2BP2 to NOTCH1, thereby impeding the proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells.	no	no	/	[267]
Quercetin	METTL3	Unknown	Cervical cancer	METTL3 promotes the proliferation and metastasis of cervical cancer cells. Quercetin enhances the sensitivity of cervical cancer cells to cisplatin by inhibiting METTL3 protein expression, hence diminishing tumor progression and improving chemotherapeutic efficacy.	Phase II Phase II Phase II	TNBC HNSC TSCC	NCT06355037 NCT05724329 NCT05456022	[234]
Simvastatin	METTL3	Unknown	Lung cancer	In lung cancer, simvastatin decreased the expression of METTL3 and consequently the m6A levels of EZH2 mRNA, thus impeding the movement and infiltration of A549 cells.	Phase II Phase II Phase II Phase II	PRAD, PAAD, BC, SCLC	NCT06437574 NCT05821556 NCT05550415 NCT04698941	[239]