YTHDF2

Summary

YTHDF2 (YTH N6-methyladenosine RNA binding protein F2, HGNC:31675) is a protein-coding gene on chromosome 1p35.3, encoding YTH domain-containing family protein 2 (Q9Y5A9). Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability. It is a selective cancer dependency (DepMap: 27.6% of cell lines).

This gene encodes a member of the YTH (YT521-B homology) superfamily containing YTH domain. The YTH domain is typical for the eukaryotes and is particularly abundant in plants. The YTH domain is usually located in the middle of the protein sequence and may function in binding to RNA. In addition to a YTH domain, this protein has a proline rich region which may be involved in signal transduction. An Alu-rich domain has been identified in one of the introns of this gene, which is thought to be associated with human longevity. In addition, reciprocal translocations between this gene and the Runx1 (AML1) gene on chromosome 21 has been observed in patients with acute myeloid leukemia. This gene was initially mapped to chromosome 14, which was later turned out to be a pseudogene. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.

Source: NCBI Gene 51441 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 58 total
• Regional missense constraint (gnomAD): 2 of 4 regions constrained (≈26% of expected missense variation)
• GTEx eGene: eQTL in 6 tissues, sQTL in 1 (q < 0.05)
• Cancer dependency (DepMap): dependent in 27.6% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.13 (highly constrained)
• MANE Select transcript: NM_016258
• Interaction hub: 2,696 STRING partners (top 3% of genes corpus-wide)
• Notable: 58 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31675
Approved symbol	YTHDF2
Name	YTH N6-methyladenosine RNA binding protein F2
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	HGRG8, NY-REN-2, CAHL
Ensembl gene	ENSG00000198492
Ensembl biotype	protein_coding
OMIM	610640
Entrez	51441

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 14 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000373812

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 2, TSL 5: 2

ENST00000373812, ENST00000468863, ENST00000474884, ENST00000475796, ENST00000476976, ENST00000478283, ENST00000496288, ENST00000541996, ENST00000542507, ENST00000856190, ENST00000976925, ENST00000976926, ENST00000976927, ENST00001058757, ENST00001102586, ENST00001102587, ENST00001102588, ENST00001119164, ENST00001126768, ENST00001145651

RefSeq mRNA: 3 — MANE Select: NM_016258 NM_001172828, NM_001173128, NM_016258

CCDS: CCDS41296, CCDS53287

Canonical transcript exons

ENST00000373812 — 5 exons

Exon	Start	End
ENSE00001065066	28768929	28769775
ENSE00001546244	28736940	28737147
ENSE00003490348	28742403	28743986
ENSE00003524053	28737658	28737682
ENSE00003547472	28738259	28738338

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 96.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.9199 / max 405.7555, expressed in 1826 samples.

Highest expression (Bgee): primordial germ cell in gonad, cortical plate, cerebellar vermis, quadriceps femoris, ganglionic eminence.

Genetic regulation across tissues (GTEx eQTL / sQTL)

YTHDF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 6 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

7 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Colon Transverse	eqtl	3.8e-04	-0.10	1:28803420:T:C
Whole Blood	eqtl	4.6e-03	-0.08	1:28775780:G:T
Esophagus Muscularis	eqtl	1.2e-02	-0.32	1:29439544:T:C
Small Intestine Terminal Ileum	eqtl	1.4e-02	-0.18	1:28839325:C:G
Nerve Tibial	eqtl	2.1e-02	-0.29	1:29630139:A:G
Cells Cultured fibroblasts	eqtl	3.5e-02	-0.07	1:28757437:TC:T
Skin Sun Exposed Lower leg	sqtl	3.6e-02	-1.07	1:29611445:C:T

FANTOM5 promoters

showing 10 of 12 alternative TSS:

Promoter ID	TPM avg	Samples expressed
1833	54.4247	1823
1834	8.9862	1780
1832	3.8899	1418
1836	1.1145	570
1835	1.0001	605
1829	0.8750	228
1837	0.8722	365
1831	0.4400	129
1838	0.1588	72
1830	0.1060	47

Top tissues by expression

showing 100 of 138 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.56	gold quality
cortical plate	UBERON:0005343	96.08	gold quality
cerebellar vermis	UBERON:0004720	95.65	gold quality
quadriceps femoris	UBERON:0001377	95.55	gold quality
ganglionic eminence	UBERON:0004023	95.42	gold quality
islet of Langerhans	UBERON:0000006	94.87	gold quality
stromal cell of endometrium	CL:0002255	94.51	gold quality
bone marrow cell	CL:0002092	94.13	gold quality
bone marrow	UBERON:0002371	94.05	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.84	gold quality
skin of abdomen	UBERON:0001416	93.54	gold quality
ventricular zone	UBERON:0003053	93.42	gold quality
endometrium	UBERON:0001295	93.31	gold quality
zone of skin	UBERON:0000014	93.23	gold quality
smooth muscle tissue	UBERON:0001135	93.21	gold quality
tonsil	UBERON:0002372	93.11	gold quality
skin of leg	UBERON:0001511	92.98	gold quality
right adrenal gland cortex	UBERON:0035827	92.98	gold quality
rectum	UBERON:0001052	92.89	gold quality
placenta	UBERON:0001987	92.80	gold quality
esophagus mucosa	UBERON:0002469	92.78	gold quality
right adrenal gland	UBERON:0001233	92.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.58	gold quality
gastrocnemius	UBERON:0001388	92.57	gold quality
left adrenal gland	UBERON:0001234	92.54	gold quality
lymph node	UBERON:0000029	92.51	gold quality
adrenal tissue	UBERON:0018303	92.34	gold quality
adrenal gland	UBERON:0002369	92.28	gold quality
muscle of leg	UBERON:0001383	92.20	gold quality
left adrenal gland cortex	UBERON:0035825	92.20	gold quality
saliva-secreting gland	UBERON:0001044	92.14	gold quality
pancreas	UBERON:0001264	92.09	gold quality
fallopian tube	UBERON:0003889	92.09	gold quality
left uterine tube	UBERON:0001303	91.99	gold quality
leukocyte	CL:0000738	91.95	gold quality
minor salivary gland	UBERON:0001830	91.92	gold quality
thoracic mammary gland	UBERON:0005200	91.92	gold quality
monocyte	CL:0000576	91.79	gold quality
gall bladder	UBERON:0002110	91.77	gold quality
duodenum	UBERON:0002114	91.68	gold quality
lung	UBERON:0002048	91.53	gold quality
vermiform appendix	UBERON:0001154	91.44	gold quality
omental fat pad	UBERON:0010414	91.41	gold quality
esophagus	UBERON:0001043	91.33	gold quality
adipose tissue	UBERON:0001013	91.27	gold quality
upper lobe of left lung	UBERON:0008952	91.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.24	gold quality
mucosa of transverse colon	UBERON:0004991	91.22	gold quality
transverse colon	UBERON:0001157	91.17	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.12	gold quality
body of pancreas	UBERON:0001150	90.99	gold quality
lower esophagus mucosa	UBERON:0035834	90.93	gold quality
right ovary	UBERON:0002118	90.92	gold quality
body of stomach	UBERON:0001161	90.90	gold quality
vagina	UBERON:0000996	90.88	gold quality
right lung	UBERON:0002167	90.87	gold quality
thymus	UBERON:0002370	90.85	gold quality
right coronary artery	UBERON:0001625	90.73	gold quality
stomach	UBERON:0000945	90.63	gold quality
spleen	UBERON:0002106	90.63	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.60	gold quality
granulocyte	CL:0000094	90.59	gold quality
ectocervix	UBERON:0012249	90.55	gold quality
intestine	UBERON:0000160	90.54	gold quality
colon	UBERON:0001155	90.53	gold quality
muscle tissue	UBERON:0002385	90.53	gold quality
small intestine	UBERON:0002108	90.41	gold quality
cortex of kidney	UBERON:0001225	90.34	gold quality
right lobe of liver	UBERON:0001114	90.24	gold quality
right testis	UBERON:0004534	90.24	gold quality
adult mammalian kidney	UBERON:0000082	90.23	gold quality
ovary	UBERON:0000992	90.21	gold quality
right lobe of thyroid gland	UBERON:0001119	90.17	gold quality
myometrium	UBERON:0001296	90.17	gold quality
multicellular organism	UBERON:0000468	90.14	gold quality
body of uterus	UBERON:0009853	90.14	gold quality
skeletal muscle tissue	UBERON:0001134	90.09	gold quality
uterine cervix	UBERON:0000002	90.07	gold quality
testis	UBERON:0000473	90.06	gold quality
kidney	UBERON:0002113	90.06	gold quality
superior frontal gyrus	UBERON:0002661	90.04	gold quality
right uterine tube	UBERON:0001302	90.00	gold quality
endocervix	UBERON:0000458	89.99	gold quality
fundus of stomach	UBERON:0001160	89.86	gold quality
left ovary	UBERON:0002119	89.84	gold quality
blood	UBERON:0000178	89.78	gold quality
urinary bladder	UBERON:0001255	89.78	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.77	gold quality
lower esophagus	UBERON:0013473	89.72	gold quality
heart left ventricle	UBERON:0002084	89.71	gold quality
descending thoracic aorta	UBERON:0002345	89.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.71	gold quality
left coronary artery	UBERON:0001626	89.68	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.68	gold quality
liver	UBERON:0002107	89.66	gold quality
heart	UBERON:0000948	89.61	gold quality
prefrontal cortex	UBERON:0000451	89.59	gold quality
left testis	UBERON:0004533	89.50	gold quality
left lobe of thyroid gland	UBERON:0001120	89.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.38	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7052	no	546.41
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	60.3	medium
Choroid plexus	tissue	43.8
Epididymis	tissue	41.2	high
Thymus	tissue	41.1
Tonsil	tissue	41.1	medium
Liver	tissue	39.4	medium
Salivary gland	tissue	37.5	medium
Breast	tissue	35.9	medium
Skin 1	tissue	35.3	medium
Parathyroid gland	tissue	34.9	not detected
Lung	tissue	33.5	high
Lymph node	tissue	33.3	medium
Hippocampal formation	tissue	32.4
Placenta	tissue	32.3	high
Rectum	tissue	31.8	high
Tongue	tissue	31.5
Thalamus	tissue	31.5
Adipose tissue	tissue	31.4	low
Spinal cord	tissue	31.4
Smooth muscle	tissue	30.7	medium
Urinary bladder	tissue	30.7	high
Superior colliculi	tissue	30.4
Spleen	tissue	30.2	medium
Cerebral cortex	tissue	30.0	medium
Colon	tissue	30.0	high
Somatosensory cortex	tissue	30.0
Midbrain	tissue	29.8
Kidney	tissue	29.7	high
Pons	tissue	29.3
Skeletal muscle	tissue	29.3	not detected
Hypothalamus	tissue	29.3
Medulla oblongata	tissue	28.9
Substantia nigra	tissue	28.7
Basal ganglia	tissue	28.4	medium
Corpus callosum	tissue	28.3
Putamen	tissue	28.1
Septum	tissue	28.1
Ventral forebrain	tissue	27.9
Occipital cortex	tissue	27.9
Esophagus	tissue	27.7	high
Motor cortex	tissue	27.7
Duodenum	tissue	27.7	high
Olfactory bulb	tissue	27.6
Testis	tissue	27.4	high
Temporal cortex	tissue	27.2
Prefrontal cortex	tissue	27.1
Retrosplenial and cingulate cortex	tissue	27.0
Periaqueductal gray	tissue	26.8
Postcentral gyrus	tissue	26.6
Entorhinal cortex	tissue	26.6
Ovary	tissue	26.5	not detected
Thyroid gland	tissue	26.2	high
Endometrium 1	tissue	26.1	low
Adrenal gland	tissue	26.1	high
Fallopian tube	tissue	26.1	medium
Stomach 1	tissue	26.0	high
Cervix	tissue	25.9	high
Cerebellum	tissue	25.9	high
Retrosplenial cortex	tissue	25.8
Vagina	tissue	25.6	high

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal hippocampus (32.4), Ventral spinal cord (31.4), Lateral funiculus (white matter) (30.3), Ventral hippocampus (29.8), Dorsal spinal cord (29.4).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting YTHDF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 124 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.132, missense Z 3.4 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000373812 splits into 4 regions with different missense tolerance; 2 are missense-constrained (≈26% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:28,737,121–28,743,432	385 / 475.8	0.81	no
1:28,743,433–28,743,816	59 / 168.9	0.35	yes (p 2.7e-17)
1:28,743,817–28,743,860	1 / 17.8	0.06	yes (p 6.8e-05)
1:28,743,861–28,768,949	38 / 60.1	0.63	no
DepMap (CRISPR cell-line fitness): dependent in 27.6% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): NB-4 (-1.451), BICR 16 (-1.324), DEL (-1.253), OCI-LY18 (-1.226), LO68 (-1.207), Daoy (-1.195), SF539 (-1.173), SU-DHL-10 (-1.165), DAN-G (-1.133), COLO-800 (-1.097), BICR 6 (-1.074), TASK1 (-1.052), SW 1990 (-1.036), EFO-21 (-1.036), EJM (-1.03).

Literature-anchored findings (GeneRIF, showing 40)

• PMID:10508479 reported that AF155095 (clone REN-2) may be involved in signal transduction and the gene is on chromosome 14. It turns out that it is the pseudogene, not the real gene, is located on chromosome 14. (PMID:10508479)
• YTHDF2 messenger RNA resulted to be mainly expressed in testis and placenta. The data suggest a possible role of this locus in human longevity. (PMID:16799135)
• m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation (PMID:24284625)
• The study presents the structure of YTH-YTHDF2 in complex with an N6-methyladenosine mononucleotide. (PMID:25412658)
• The basic residues K416 and R527 on the surface of the YTH domain of YTHDF2 are involved in binding to the RNA backbone, and residues W432 and W486 within the hydrophobic pocket contribute to the specific recognition of N6-methyladenosine. (PMID:25412661)
• binding affinities of the YTH domains of three human proteins and yeast YTH domain protein Pho92 (PMID:26318451)
• The authors found that the overexpression of YTHDF proteins in cells inhibited HIV-1 infection mainly by decreasing HIV-1 reverse transcription, while knockdown of YTHDF1-3 in cells had the opposite effects. Moreover, silencing the N(6)-methyladenosine writers decreased HIV-1 Gag protein expression in virus-producing cells, while silencing the N(6)-methyladenosine erasers increased Gag expression. (PMID:27371828)
• YTHDF2 recruits the CCR4-NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. (PMID:27558897)
• miR-145 modulates N(6)-methyladenosine levels by targeting the 3’-UTR of YTHDF2 mRNA in hepatocellular carcinoma cells (PMID:28104805)
• YTHDF2 knockdown significantly increases the total YAP expression, but inhibits TGF-beta/Smad signaling, indicating that YTHDF2 regulates EMT probably via YAP signaling. (PMID:29135329)
• apoptosis ratio of YTHDF2-shRNA-expressing MGC-803 cells was significantly higher compared with the control groups (PMID:29382422)
• YTHDF2 may act as a tumor suppressor to repress cell proliferation and growth by destabilizing the EGFR mRNA in hepatocellular carcinoma cells. (PMID:30423408)
• We also find that a subset of m(6)A-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. (PMID:30930054)
• Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. (PMID:31031138)
• YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation. (PMID:31504235)
• Binding to m(6)A RNA promotes YTHDF2-mediated phase separation. (PMID:31642031)
• Our results have characterized the m(6)A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression. (PMID:31735169)
• YTHDF2 Binds to 5-Methylcytosine in RNA and Modulates the Maturation of Ribosomal RNA. (PMID:31815440)
• Molecular Mechanisms Driving mRNA Degradation by m(6)A Modification. (PMID:31964509)
• m(6) A RNA methylation regulators contribute to malignant progression in rectal cancer. (PMID:32043594)
• METTL3/YTHDF2 m(6) A axis promotes tumorigenesis by degrading SETD7 and KLF4 mRNAs in bladder cancer. (PMID:32126149)
• Results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in induced pluripotent stem cells and facilitate their rapid and coordinated up-regulation during neural induction. (PMID:32169943)
• YTHDF2 stability is maintained by CDK1.YTHDF2 promotes mRNA decay during cell cycle.Proteolysis pathway of YTHDF2. (PMID:32267835)
• YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. (PMID:32366907)
• [Knockdown of YTH N(6)-methyladenosine RNA binding protein 2 (YTHDF2) inhibits cell proliferation and promotes apoptosis in cervical cancer cells]. (PMID:32389174)
• The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus. (PMID:32583611)
• Decreased ALKBH5, FTO, and YTHDF2 in Peripheral Blood Are as Risk Factors for Rheumatoid Arthritis. (PMID:32884942)
• YTHDF2/3 Are Required for Somatic Reprogramming through Different RNA Deadenylation Pathways. (PMID:32905781)
• YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells. (PMID:32948220)
• YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. (PMID:33121495)
• METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5. (PMID:33411363)
• EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. (PMID:33420027)
• SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs. (PMID:33577677)
• FTO regulates myoblast proliferation by controlling CCND1 expression in an m(6)A-YTHDF2-dependent manner. (PMID:33651996)
• FBW7 suppresses ovarian cancer development by targeting the N(6)-methyladenosine binding protein YTHDF2. (PMID:33658012)
• N-methyladenosine reader YTHDF2-mediated long noncoding RNA FENDRR degradation promotes cell proliferation in endometrioid endometrial carcinoma. (PMID:33692441)
• Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. (PMID:33726814)
• YTHDF2 is a potential target of AML1/ETO-HIF1alpha loop-mediated cell proliferation in t(8;21) AML. (PMID:33958724)
• RNA m(6)A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/beta-catenin signaling. (PMID:33980824)
• PBRM1 Cooperates with YTHDF2 to Control HIF-1alpha Protein Translation. (PMID:34200988)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ythdf2	ENSDARG00000014498
mus_musculus	Ythdf2	ENSMUSG00000040025
rattus_norvegicus	Ythdf2	ENSRNOG00000010892
drosophila_melanogaster	Ythdf	FBGN0039261

Paralogs (3): YTHDC1 (ENSG00000083896), YTHDF1 (ENSG00000149658), YTHDF3 (ENSG00000185728)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2444233) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 15 distinct phenotype terms.

Mouse phenotype (MP)	Records
female infertility	2
oligozoospermia	2
preweaning lethality, incomplete penetrance	2
impaired fertilization	1
seminiferous tubule degeneration	1
abnormal spermatogenesis	1
reduced male fertility	1
male infertility	1
asthenozoospermia	1
abnormal Sertoli cell morphology	1
maternal effect	1
abnormal metabolism	1
teratozoospermia	1
increased male germ cell apoptosis	1
decreased sperm progressive motility	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RFL8	100.0%	Diamond
Macaca fascicularis	Q4R5D9	99.8%	Diamond
Bos taurus	Q0VCZ3	98.3%	Diamond
Arabidopsis thaliana	Q9LJE5	73.5%	Diamond
Cryphonectria parasitica EP155	A0A9P4XWM4	51.7%	Diamond
Pyricularia oryzae 70-15	G4MRQ6	49.8%	Diamond
Saccharomyces cerevisiae S288C	Q06390	43.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GMEB1	protein-coding	10691
RAB42	protein-coding	115273
RNU11	snRNA	26824
TAF12	protein-coding	6883
SNORA16A	snoRNA	692073
SNHG12	ncRNA	85028
TAF12-DT	ncRNA	105378616
OPRD1	protein-coding	4985
EPB41	protein-coding	2035
TMEM200B	protein-coding	399474
MECR	protein-coding	51102
SRSF4	protein-coding	6429

Protein

Protein identifiers

YTH domain-containing family protein 2 — Q9Y5A9 (reviewed: Q9Y5A9)

Alternative names: CLL-associated antigen KW-14, High-glucose-regulated protein 8, Renal carcinoma antigen NY-REN-2

All UniProt accessions (3): Q9Y5A9, S4R3J8, S4R3V3

UniProt curated annotations — full annotation on UniProt →

Function. Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability. M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing. Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT and ribonuclease P/MRP complexes, depending on the context. The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation. M6A-containing mRNAs containing a binding site for RIDA/HRSP12 (5’-GGUUC-3’) are preferentially degraded by endoribonucleolytic cleavage: cooperative binding of RIDA/HRSP12 and YTHDF2 to transcripts leads to recruitment of the ribonuclease P/MRP complex. Other m6A-containing mRNAs undergo deadenylation via direct interaction between YTHDF2 and CNOT1, leading to recruitment of the CCR4-NOT and subsequent deadenylation of m6A-containing mRNAs. Required maternally to regulate oocyte maturation: probably acts by binding to m6A-containing mRNAs, thereby regulating maternal transcript dosage during oocyte maturation, which is essential for the competence of oocytes to sustain early zygotic development. Also required during spermatogenesis: regulates spermagonial adhesion by promoting degradation of m6A-containing transcripts coding for matrix metallopeptidases. Also involved in hematopoietic stem cells specification by binding to m6A-containing mRNAs, leading to promote their degradation. Also acts as a regulator of neural development by promoting m6A-dependent degradation of neural development-related mRNA targets. Inhibits neural specification of induced pluripotent stem cells by binding to methylated neural-specific mRNAs and promoting their degradation, thereby restraining neural differentiation. Regulates circadian regulation of hepatic lipid metabolism: acts by promoting m6A-dependent degradation of PPARA transcripts. Regulates the innate immune response to infection by inhibiting the type I interferon response: acts by binding to m6A-containing IFNB transcripts and promoting their degradation. May also act as a promoter of cap-independent mRNA translation following heat shock stress: upon stress, relocalizes to the nucleus and specifically binds mRNAs with some m6A methylation mark at their 5’-UTR, protecting demethylation of mRNAs by FTO, thereby promoting cap-independent mRNA translation. Regulates mitotic entry by promoting the phase-specific m6A-dependent degradation of WEE1 transcripts. Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules. May also recognize and bind RNAs modified by C5-methylcytosine (m5C) and act as a regulator of rRNA processing. (Microbial infection) Promotes viral gene expression and replication of polyomavirus SV40: acts by binding to N6-methyladenosine (m6A)-containing viral RNAs. (Microbial infection) Promotes viral gene expression and virion production of kaposis sarcoma-associated herpesvirus (KSHV) at some stage of the KSHV life cycle (in iSLK.219 and iSLK.BAC16 cells). Acts by binding to N6-methyladenosine (m6A)-containing viral RNAs.

Subunit / interactions. Interacts with CNOT1; interaction is direct and promotes recruitment of the CCR4-NOT complex. Interacts with YTHDF3. Interacts with RIDA/HRSP12; interaction leads to recruitment of the ribonuclease P/MRP complex.

Subcellular location. Cytoplasm. Cytosol. P-body. Stress granule. Nucleus.

Tissue specificity. Highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation.

Post-translational modifications. Ubiquitinated by the SCF(SKP2) complex, leading to its degradation.

Domain organisation. The disordered regions have the ability to interact with each other and to ‘phase separate’ into liquid droplets within the cytosol following binding to mRNAs containing multiple m6A-modified residues. This leads to the partition of m6A-containing mRNAs into membraneless compartments, where mRNAs may be stored, degraded or used to transport mRNAs to dendritic arbors in neurons.

Induction. Following heat shock stress.

Similarity. Belongs to the YTHDF family. YTHDF2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5A9-1	1	yes
Q9Y5A9-2	2

RefSeq proteins (3): NP_001166299, NP_001166599, NP_057342* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007275	YTH_domain	Domain
IPR045168	YTH_prot	Family

Pfam: PF04146

UniProt features (50 total): modified residue 9, mutagenesis site 7, strand 7, binding site 6, helix 5, compositionally biased region 4, region of interest 4, sequence variant 2, turn 2, initiator methionine 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

29 structures by resolution:

PDB	Title	Method	Resolution (Å)
7R5L	Crystal structure of YTHDF2 with compound YLI_DC1_015	X-RAY DIFFRACTION	1.7
7Z5M	Crystal structure of YTHDF2 with compound YLI_DC1_008	X-RAY DIFFRACTION	1.7
9QFL	Crystal structure of YTHDF2 in complex with compound 15 (AI-DF2-68)	X-RAY DIFFRACTION	1.7
7R5W	Crystal structure of YTHDF2 with compound YLI_DF_029	X-RAY DIFFRACTION	1.75
7YX6	Crystal structure of YTHDF2 with compound YLI_DF_027	X-RAY DIFFRACTION	1.8
7Z7B	Crystal structure of YTHDF2 with compound YLI_DC1_003	X-RAY DIFFRACTION	1.8
7Z54	Crystal structure of YTHDF2 with compound YLI_DC1_006	X-RAY DIFFRACTION	1.82
7Z4U	Crystal structure of YTHDF2 with compound YLI_DF_028	X-RAY DIFFRACTION	1.83
7YXE	Crystal structure of YTHDF2 with compound ZA_143	X-RAY DIFFRACTION	1.85
9QEL	Crystal structure of YTHDF2 in complex with compound 4 (AI-DF2-13)	X-RAY DIFFRACTION	1.86
7Z26	Crystal structure of YTHDF2 YTH domain in complex with m6A RNA	X-RAY DIFFRACTION	1.9
7Z8W	Crystal structure of YTHDF2 with compound YLI_DC1_018	X-RAY DIFFRACTION	1.9
7Z92	Crystal structure of YTHDF2 with compound YLI_DF_024	X-RAY DIFFRACTION	1.91
9QFI	Crystal structure of YTHDF2 in complex with compound 6 (AI-DF2-47)	X-RAY DIFFRACTION	1.91
7YWB	Crystal structure of YTHDF2 in complex with N6-Methyladenine	X-RAY DIFFRACTION	1.92
7Z7F	Crystal structure of YTHDF2 with compound YLI_DC1_005	X-RAY DIFFRACTION	1.95
7Z8X	Crystal structure of YTHDF2 with compound YLI_DC1_017	X-RAY DIFFRACTION	1.96
7Z8P	Crystal structure of YTHDF2 with compound ZA_166	X-RAY DIFFRACTION	1.97
7Z93	Crystal structure of YTHDF2 with compound YLI_DF_022	X-RAY DIFFRACTION	1.97
9QEO	Crystal structure of YTHDF2 in complex with compound 5 (AI-DF2-36)	X-RAY DIFFRACTION	1.98
7R5F	Crystal structure of YTHDF2 with compound YLI_DF_012	X-RAY DIFFRACTION	2
7ZG4	Crystal structure of YTHDF2 with compound YLI_DF_042	X-RAY DIFFRACTION	2.01
4RDN	Structure of YTH-YTHDF2 in complex with m6A	X-RAY DIFFRACTION	2.1
7BIK	Crystal structure of YTHDF2 in complex with m6Am	X-RAY DIFFRACTION	2.1
4WQN	Crystal structure of N6-methyladenosine RNA reader YTHDF2	X-RAY DIFFRACTION	2.12
4RDO	Structure of YTH-YTHDF2 in the free state	X-RAY DIFFRACTION	2.15
7A1V	Crystal structure of YTHDF2 in complex with m1A	X-RAY DIFFRACTION	2.2
9QEM	Crystal structure of YTHDF2 in complex with compound 3 (AI-DF2-11)	X-RAY DIFFRACTION	2.26
9QIU	Crystal structure of YTHDF2 in complex with compound 13 (AI-DF2-56)	X-RAY DIFFRACTION	2.46

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5A9-F1	61.14	0.31

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; cytoplasmic bodies

Antibody reliability (HPA): IH approved · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6)

Position	Role
416–418	RNA
422	RNA
432–433	RNA
462	RNA
486	RNA
491	RNA

Post-translational modifications (9)

Type	Positions
N-acetylserine	2
Phosphoserine	2, 4, 5, 22, 39, 196, 359, 394

Mutagenesis-validated functional residues (7)

Position	Phenotype
411	slightly decreased binding to rnas.
416	decreased binding to rnas.
432	reduced binding to n6-methyladenosine (m6a)-containing rnas. reduced ability to undergo liquid-liquid phase separation. reduced binding to …
441	slightly decreased binding to rnas.
486	reduced binding to n6-methyladenosine (m6a)-containing rnas. reduced ability to undergo liquid-liquid phase separation; when associated …
491	reduced binding to n6-methyladenosine (m6a)-containing rnas.
527	decreased binding to rnas.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 313 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, RORA1_01, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_STEM_CELL_DIFFERENTIATION, GOBP_OOGENESIS, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (27): oocyte maturation (GO:0001556), mRNA catabolic process (GO:0006402), humoral immune response (GO:0006959), gamete generation (GO:0007276), spermatogonial cell division (GO:0007284), regulation of cell adhesion (GO:0030155), cytoplasmic stress granule assembly (GO:0034063), regulation of mRNA stability (GO:0043488), innate immune response (GO:0045087), negative regulation of Notch signaling pathway (GO:0045746), embryonic morphogenesis (GO:0048598), regulation of neurogenesis (GO:0050767), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), mRNA destabilization (GO:0061157), organelle assembly (GO:0070925), hematopoietic stem cell proliferation (GO:0071425), endothelial to hematopoietic transition (GO:0098508), regulation of hematopoietic stem cell differentiation (GO:1902036), regulation of meiotic cell cycle process involved in oocyte maturation (GO:1903538), positive regulation of cap-independent translational initiation (GO:1903679), regulation of rRNA processing (GO:2000232), negative regulation of stem cell differentiation (GO:2000737), immune system process (GO:0002376), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), oogenesis (GO:0048477), cell division (GO:0051301)

GO Molecular Function (5): RNA binding (GO:0003723), mRNA binding (GO:0003729), C5-methylcytidine-containing RNA reader activity (GO:0062153), N6-methyladenosine-containing RNA reader activity (GO:1990247), protein binding (GO:0005515)

GO Cellular Component (6): P-body (GO:0000932), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), cytoplasmic ribonucleoprotein granule (GO:0036464)

GO top-level categories

57 GO namespaces:

Category	Terms
RNA binding	3
negative regulation of gene expression	2
immune response	2
protein-RNA adaptor activity	2
cytoplasmic ribonucleoprotein granule	2
cellular anatomical structure	2
cytoplasm	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
RNA catabolic process	1
mRNA metabolic process	1
sexual reproduction	1
multicellular organismal reproductive process	1
spermatogenesis	1
cell division	1
cell adhesion	1
regulation of cellular process	1
membraneless organelle assembly	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
defense response to symbiont	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
anatomical structure morphogenesis	1
embryo development	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
regulation of mRNA stability	1
RNA destabilization	1
positive regulation of mRNA catabolic process	1
organelle organization	1
cellular component assembly	1
hemopoiesis	1
stem cell proliferation	1
cell morphogenesis	1
delamination	1
hematopoietic stem cell differentiation	1
regulation of hematopoietic progenitor cell differentiation	1
regulation of stem cell differentiation	1
regulation of cell cycle process	1
meiotic cell cycle process involved in oocyte maturation	1
regulation of reproductive process	1
cap-independent translational initiation	1
regulation of cap-independent translational initiation	1
positive regulation of cytoplasmic translational initiation	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
ribonucleoprotein granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 19 of 38 annotations. The rest are phylogenetic / computational / electronic (IEA).

19 experimentally-supported GO terms:

GO term	NS	Evidence
cytoplasmic stress granule assembly	BP	direct assay
mRNA catabolic process	BP	direct assay
mRNA destabilization	BP	direct assay
negative regulation of stem cell differentiation	BP	mutant phenotype
negative regulation of type I interferon-mediated signaling pathway	BP	mutant phenotype
organelle assembly	BP	direct assay
positive regulation of cap-independent translational initiation	BP	direct assay
regulation of mRNA stability	BP	direct assay
regulation of neurogenesis	BP	mutant phenotype
regulation of rRNA processing	BP	mutant phenotype
P-body	CC	direct assay
cytoplasm	CC	direct assay
cytoplasmic ribonucleoprotein granule	CC	direct assay
cytoplasmic stress granule	CC	direct assay
cytosol	CC	direct assay
nucleus	CC	direct assay
C5-methylcytidine-containing RNA reader activity	MF	direct assay
N6-methyladenosine-containing RNA reader activity	MF	direct assay
RNA binding	MF	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 2,696 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YTHDF2	METTL14	Q9HCE5	915
YTHDF2	WTAP	Q15007	899
YTHDF2	METTL3	Q86U44	898
YTHDF2	ALKBH5	Q6P6C2	895
YTHDF2	FTO	Q9C0B1	888
YTHDF2	VIRMA	Q69YN4	887
YTHDF2	ZC3H13	Q5T200	862
YTHDF2	RBM15	Q96T37	857
YTHDF2	HNRNPC	P07910	800
YTHDF2	RBM15B	Q8NDT2	800
YTHDF2	HNRNPA2B1	P22626	792
YTHDF2	METTL16	Q86W50	785
YTHDF2	IGF2BP1	Q9NZI8	779
YTHDF2	IGF2BP2	Q9Y6M1	773
YTHDF2	RBMX	P38159	771

IntAct

Human interaction partners of YTHDF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
ENG	direct interaction	0.440	1
IRAK2	physical association	0.400	1

BioGRID (643 interactions; top human partners by supporting records in a sample of 600 records): YTHDF3 (Proximity Label-MS; 8 records), HSP90AB1 (Cross-Linking-MS (XL-MS); 5 records), YTHDF1 (Proximity Label-MS; 5 records), G3BP1 (Affinity Capture-MS; 4 records), STUB1 (Affinity Capture-Western; 4 records), CAPRIN1 (Proximity Label-MS; 3 records), CSDE1 (Proximity Label-MS; 3 records), DDX6 (Proximity Label-MS; 3 records), FBXW7 (Affinity Capture-MS; 3 records), FUBP3 (Proximity Label-MS; 3 records), FXR1 (Proximity Label-MS; 3 records), FXR2 (Proximity Label-MS; 3 records), NUFIP2 (Proximity Label-MS; 3 records), PABPC1 (Proximity Label-MS; 3 records), PARK2 (Affinity Capture-MS; 3 records)

Disease & clinical

Genetic variants

Variant evidence for YTHDF2: 58 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

58 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 20 predictions of 400):

Position(s)	Effect	Δscore	Sites
1:28737609	acceptor_gain	1.0000
1:28737618–28737619	acceptor_gain	1.0000	2
1:28737683	donor_loss	1.0000	2
1:28768920	acceptor_gain	1.0000
1:28768927–28768928	acceptor_loss	1.0000	4
1:28737148–28737149	donor_loss	0.9900	6
1:28737624	acceptor_gain	0.9900
1:28738261	acceptor_gain	0.9900
1:28768924	acceptor_gain	0.9900
1:28768927	acceptor_loss	0.9900

AlphaMissense

1,937 missense substitutions predicted likely pathogenic (of 3,827 scored), across 427 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M473	9	0.995	1.000
D421	8	1.000	1.000
D422	8	1.000	1.000
H424	8	1.000	1.000
N462	8	1.000	1.000
D504	8	1.000	1.000
D528	8	1.000	1.000
D556	8	1.000	1.000
S417	8	0.999	1.000
N439	8	0.999	1.000
S460	8	0.999	1.000
H466	8	0.999	1.000
F467	8	0.999	1.000
S434	8	0.998	1.000
F495	8	0.998	1.000
N517	8	0.998	1.000
F554	8	0.998	1.000
D555	8	0.997	1.000
F557	8	0.997	1.000
S464	8	0.996	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.94e-09
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.45e-07

Disease associations

OMIM: gene MIM:610640 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295992 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

24 measured of 24 human assays (25 total across all organisms); most potent 24 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[(cyclopropylamino)methyl]-N-(pyridin-3-ylmethyl)pyridin-2-amine	KI	0.09 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-[(3,4-dimethoxyphenyl)methyl]pyridin-2-amine	KI	0.123 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-(1-phenylethyl)pyridin-2-amine	KI	0.129 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-[[4-(trifluoromethyl)phenyl]methyl]pyridin-2-amine	KI	0.162 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-[(4-methoxyphenyl)methyl]pyridin-2-amine	KI	0.164 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(dimethylamino)methyl]-N-(1-phenylethyl)pyridin-2-amine	KI	0.209 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(dimethylamino)methyl]-N-[(4-methoxyphenyl)methyl]pyridin-2-amine	KI	0.214 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-[(2,4-dimethoxyphenyl)methyl]pyridin-2-amine	KI	0.229 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-(4-fluoro-2-pyridinyl)pyridin-2-amine	KI	0.236 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(dimethylamino)methyl]-N-[[4-(trifluoromethyl)phenyl]methyl]pyridin-2-amine	KI	0.266 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-[(2,6-difluorophenyl)methyl]pyridin-2-amine	KI	0.281 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-[(3,4-difluorophenyl)methyl]pyridin-2-amine	KI	0.285 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(dimethylamino)methyl]-N-[(4-fluorophenyl)methyl]pyridin-2-amine	KI	0.391 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
N-[5-[(cyclopropylamino)methyl]-2-pyridinyl]-2,6-difluoropyridin-3-amine	KI	0.399 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-(3,5-dimethoxyphenyl)pyridin-2-amine	KI	0.473 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(dimethylamino)methyl]-N-(3,4-dimethylphenyl)pyridin-2-amine	KI	0.605 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-methyl-N-[[4-(trifluoromethyl)phenyl]methyl]pyridin-2-amine	KI	0.615 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-(3,4-dimethylphenyl)pyridin-2-amine	KI	1.42 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
5-[(cyclopropylamino)methyl]-N-(2-methylsulfanylphenyl)pyridin-2-amine	KI	13.4 nM	US-20230322715: BROAD SPECTRUM ANTI-CANCER COMPOUNDS
CHEMBL5542345	IC50	89000 nM
CHEMBL5205586	IC50	161000 nM
CHEMBL5201513	IC50	161000 nM
CHEMBL5177286	IC50	174000 nM
CHEMBL5192478	IC50	379000 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 7 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.17	Kd	68.45	nM	CHEMBL3752910
7.17	ED50	68.45	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 33 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149967: Binding affinity to human YTHDF2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0684	uM

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, increases stability, increases activity, affects binding (+3 more)	7
bisphenol A	decreases expression, increases expression, affects cotreatment, decreases methylation	4
N-methyladenosine	decreases expression, increases abundance, affects binding, decreases reaction	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	increases mutagenesis, increases expression, affects reaction	2
Benzo(a)pyrene	increases methylation, increases expression	2
Indomethacin	decreases expression, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
trichostatin A	affects expression	1
cadmium sulfate	increases expression	1
fumonisin B1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-phenylbutyric acid	decreases expression	1
ICG 001	decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Arsenic Trioxide	increases response to substance	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Acetylcysteine	affects binding, decreases reaction, increases reaction	1
Caffeine	affects phosphorylation	1
Dactinomycin	affects reaction, decreases stability	1
Dexamethasone	increases expression, affects cotreatment	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118957	Binding	Binding affinity to YTHDF2 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8RX	Abcam HCT 116 YTHDF2 KO	Cancer cell line	Male
CVCL_B9UF	Abcam A-549 YTHDF2 KO	Cancer cell line	Male
CVCL_F5AD	EDITGENE YTHDF2 Knockout HCT116 Cell Line	Cancer cell line	Male
CVCL_TY47	HAP1 YTHDF2 (-) 1	Cancer cell line	Male
CVCL_XV20	HAP1 YTHDF2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for YTHDF2 across ~30M SureChEMBL compounds — explore on Sugi Predict.