m6A-centered Crosstalk Information

Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03353
 [1], [2]
Histone modification H3K27ac p300 WTAP Direct Enhancement m6A modification DKK3 DKK3 WTAP Methylation : m6A sites
m6A Modification:
m6A Regulator Wilms tumor 1-associating protein (WTAP) WRITER
 Regulator Info 
m6A Target Dickkopf-related protein 3 (DKK3)
 Targert Gene 
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Histone acetyltransferase p300 (P300) WRITER View Details
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac) View Details
Downstream Gene WTAP View Details
Crosstalk Relationship Histone modification  →  m6A Enhancement
Crosstalk Mechanism histone modification directly impacts m6A modification through modulating the level of m6A regulator
Crosstalk Summary Histone acetyltransferase p300 promotes WTAP transcription through Histone H3 lysine 27 acetylation (H3K27ac). WTAP-mediated N6-methyladenosine modification of NLRP3 mRNA in kidney injury of diabetic nephropathy.WTAP expression in HK-2 cells was examined with the introduction of C646, a histone acetyltransferase p300 inhibitor.the expression change pattern of Dickkopf-related protein 3 (DKK3) under DN circumstances is in line with those of METTL14 and WTAP. DKK3's m6A methylation sites were confirmed to be located in the 3'UTR region, which is how METTL14 and WTAP improved DKK3's mRNA stability. Finally, YTHDF1, a m6A reader, was demonstrated to recognize m6A-methylated DKK3 and promote DKK3 expression.
Responsed Disease Diabetic nephropathy ICD-11: GB61.Z
 Disease Info 
Responsed Drug SETDB1-TTD-IN-1
 Drug Info 
In-vitro Model
 HK-2 [Human kidney] Normal Homo sapiens CVCL_0302
In-vivo Model Female mice (8 weeks old, 20-25 g) on a C57BL/6J background were fasted for 12 h but were allowed to drink water freely. They were then injected intraperitoneally with 50 mg/kg body weight of freshly dissolved STZ in sterile PBS for four consecutive days. Mice were given sterile PBS alone in the same way as an untreated control. The mice's blood glucose levels were assessed two weeks after their most recent treatment. Mice that exhibited glucose levels greater than 201 mg/dL were classified as successful hyperglycemic models and were utilized in subsequent studies. Five months after the final dose of STZ, the mice were euthanized, and the renal tissues were collected for pathological examination to confirm the successful establishment of the model of diabetes nephropathy induced by hyperglycemia. All animal experiments were performed according to the guidelines of the Institutional Animal Care and Use Committee at the China Pharmaceutical University. Isoflurane was used to anesthetize mice.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Dickkopf-related protein 3 (DKK3) 1 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name REIC gene therapy Phase 1/2 [3]
MOA Modulator
External Link
TTD: D0D2XA
Histone acetyltransferase p300 (P300) 2 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name CCS1477 Phase 1/2 [4]
Synonyms
CCS-1477; CBP-IN-1; 2222941-37-7; (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one; SCHEMBL20094038; SCHEMBL21515367; SCHEMBL22134021; EX-A3687; NSC818619; NSC-818619; HY-111784; CS-0091862; (S)-1-(3,4-Difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one
    Click to Show/Hide
MOA Inhibitor
External Link
CID: 134457551
TTD: DIY4C2
 Compound Name FT-7051 Phase 1 [5]
MOA Inhibitor
External Link
TTD: DT8IL6
GB61: Chronic kidney disease 15 Compound(s) Regulating the Disease Click to Show/Hide the Full List
 Compound Name Finerenone Approved [6]
Synonyms
UNII-DE2O63YV8R; BAY 94-8862; 1050477-31-0; BAY94-8862; DE2O63YV8R; Finerenone [USAN:INN]; Finerenone (JAN/USAN/INN); SCHEMBL8157011; GTPL8678; DTXSID10146928; J3.584.878I; D10633; 1,6-Naphthyridine-3-carboxamide, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-, (4S)-;1,6-Naphthyridine-3-carboxamide, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-, (4S)-; 1,6-Naphthyridine-3-carboxamide, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-, (4S)-; (4S)-4-(4-cyano-2-metho
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External Link
CID: 60150535
TTD: D0NV5O
 Compound Name Doxercalciferol Approved [7]
Synonyms
Doxcercalciferol; Hectorol; Doxercalciferol [INN]; TSA 840; BCI-101; Doxercalciferol (INN); Hectorol (TN); (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5R)-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol; (5Z,7E,22E)-9,10-Secoergosta-5,7,10(19),22-tetraene-1alpha,3beta-diol; 1-Hydroxyergocalciferol; 1-alpha-Hydroxyvitamin D2; 1alpha-Hydroxyergocalciferol; 1alpha-OH-D2; 9,10-Secoergosta-5,7,10(19),22-tetraene-1,3-diol,(1-alpha,3-beta,5Z,7E,22E)
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External Link
CID: 5281107
TTD: D0G5CF
DrugBank: DB06410
 Compound Name Ferumoxytol Approved [8]
Synonyms
MAGNETITE; Magnetic oxide; Ferrosoferric oxide; Magnetite (Fe3O4); Magnetic Black; Iron Black; Fenosoferric oxide; Black Iron BM; Meramec M 25; Black Gold F 89; RB-BL; 11557 Black; CCRIS 4376; H 3S; EPT 500; EINECS 215-169-8; KN 320; 1309-38-2; iron(ii; ferro ferric oxide; ferric ferrous oxide; Iron ores, magnetite; Ferumoxytol [USAN]; Eisen(II,III)-oxid; KBC 100 (mineral); Code 7228; CHEBI:50821; 1317-61-9 (Parent); LS-88610; 174794-75-3; 122303-97-3; 90577-09-6; 73904-98-0; 151820-32-5; 137263-94-6; 124364-57-4
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External Link
CID: 14789
TTD: D06CTM
 Compound Name Ferric citrate Approved [9]
Synonyms
Nephoxil; Serene; Zerenex; JTT-751; KRX-0502; PBF-1681; Hyperphosphatemia therapy, Panion/Keryx
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External Link
CID: 61300
TTD: D04CJL
DrugBank: DB09162
 Compound Name REACT Phase 3 [10]
External Link
TTD: D2QVG7
 Compound Name US-APR2020 Phase 2/3 [11]
External Link
TTD: D3YKX2
 Compound Name ALLN-346 Phase 2 [12]
External Link
TTD: DG31WX
 Compound Name Runcaciguat Phase 2 [13]
Synonyms
(3S)-3-(4-Chloro-3-(((2S,3R)-2-(4-chlorophenyl-4,4,4- trifluoro-3-methylbutanoyl)amino)phenyl)-3- cyclopropylpropanoic acid; (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid; (3S)-3-[4-chloro-3-[[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino]phenyl]-3-cyclopropylpropanoic acid; 1402936-61-1; 5EZ01YDT5S; AC-37098; AKOS040742586; BAY 1101042; BAY1101042; BAY-1101042; BENZENEPROPANOIC ACID, 4-CHLORO-3-(((2S,3R)-2-(4-CHLOROPHENYL)-4,4,4-TRIFLUORO-3-METHYL-1-OXOBUTYL)AMINO)-.BETA.-CYCLOPROPYL-, (.BETA.S)-; Benzenepropanoic acid, 4-chloro-3-(((2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methyl-1-oxobutyl)amino)-beta-cyclopropyl-, (betaS)-; CHEMBL4650322; compound 45 [PMID: 33872507]; CS-0086784; GTPL12359; HY-109136; MS-29070; Runcaciguat; Runcaciguat [INN]; SCHEMBL20075857; UNII-5EZ01YDT5S; XZ7
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External Link
CID: 134440946
TTD: D2RG4D
 Compound Name GCS-100 Phase 2 [14]
External Link
TTD: D0JW0V
 Compound Name Neo-Kidney Augment Phase 2 [15]
External Link
TTD: D06XFV
 Compound Name LY-2623091 Phase 2 [16]
Synonyms
Chronic renal disease therapy, Eli Lilly
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External Link
CID: 42636651
TTD: D05RZE
DrugBank: DB15367
 Compound Name AZD1772//RDX5791 Phase 2 [17]
External Link
TTD: D04AIB
 Compound Name LY3016859 Phase 1/2 [18]
Synonyms
TGF-alpha.epiregulin mAb
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External Link
TTD: D08EIK
 Compound Name ION532 Phase 1 [19]
Synonyms
AZD2373
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External Link
TTD: DR07FQ
 Compound Name MEDI8367 Phase 1 [20]
External Link
TTD: D37AYZ
References
Ref 1 WTAP-mediated N(6)-methyladenosine modification of NLRP3 mRNA in kidney injury of diabetic nephropathy. Cell Mol Biol Lett. 2022 Jun 27;27(1):51. doi: 10.1186/s11658-022-00350-8.
Ref 2 WTAP and METTL14 regulate the m6A modification of DKK3 in renal tubular epithelial cells of diabetic nephropathy. Biochem Biophys Res Commun. 2024 Dec 17;738:150524. doi: 10.1016/j.bbrc.2024.150524. Epub 2024 Aug 9.
Ref 3 Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer. J Gastroenterol Hepatol. 2014 May;29(5):973-83.
Ref 4 Targeting the p300/CBP Axis in Lethal Prostate Cancer. Cancer Discov. 2021 May;11(5):1118-1137. doi: 10.1158/2159-8290.CD-20-0751. Epub 2021 Jan 11.
Ref 5 Clinical pipeline report, company report or official report of FORMA Therapeutics.
Ref 6 FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 215341.
Ref 7 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2790).
Ref 8 ClinicalTrials.gov (NCT01942460) Ferumoxytol for Iron-Deficiency Anemia in Chronic Kidney Disease and Peritoneal Dialysis Patients. U.S. National Institutes of Health.
Ref 9 ClinicalTrials.gov (NCT02268994) KRX-0502 (Ferric Citrate) for the Treatment of IDA in Adult Subjects With NDD-CKD. U.S. National Institutes of Health.
Ref 10 ClinicalTrials.gov (NCT05099770) A Phase 3 Randomized Controlled Study of Renal Autologous Cell Therapy (REACT) in Subjects With Type 2 Diabetes and Chronic Kidney Disease (REGEN-006). U.S.National Institutes of Health.
Ref 11 ClinicalTrials.gov (NCT05407389) An Open-Label Rollover Extension Phase 2 Clinical Trial To Evaluate The Long-Term Safety And Efficacy Of KT-301 (Formerly US-APR2020) In Subjects With CKD IV Completing The US-APR2020-01 Study. U.S.National Institutes of Health.
Ref 12 ClinicalTrials.gov (NCT04987294) A Randomized, Double-Blind, Placebo-Controlled Study of ALLN-346 (Engineered Urate Oxidase) in Hyperuricemic Subjects With Gout and Mild to Moderate Chronic Kidney Disease. U.S.National Institutes of Health.
Ref 13 ClinicalTrials.gov (NCT04507061) A Randomized, Double-blind, Placebo-controlled, Multi-center Study to Assess the Safety and Efficacy of Individually Titrated Oral Doses of Runcaciguat in Subjects With Clinical Diagnosis of Chronic Kidney Disease With Diabetes and/or Hypertension and at Least One Cardiovascular Comorbidity. U.S.National Institutes of Health.
Ref 14 ClinicalTrials.gov (NCT01843790) A Phase 2a Study of Weekly Doses of GCS-100 in Patients With Chronic Kidney Disease. U.S. National Institutes of Health.
Ref 15 ClinicalTrials.gov (NCT02525263) Autologous Neo-Kidney Augment (NKA) in Patients With Type 2 Diabetes and Chronic Kidney Disease (CKD) (RMCL-CL001). U.S. National Institutes of Health.
Ref 16 ClinicalTrials.gov (NCT02194465) A Study of LY2623091 in Participants With High Blood Pressure. U.S. National Institutes of Health.
Ref 17 Clinical pipeline report, company report or official report of Ardelyx.
Ref 18 ClinicalTrials.gov (NCT01774981) Study of LY3016859 in Participants With Diabetic Nephropathy. U.S. National Institutes of Health.
Ref 19 ClinicalTrials.gov (NCT05351047) A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2373 Following Multiple Ascending Dose Administration to Healthy Male Participants of Sub-Saharan West African Ancestry. U.S.National Institutes of Health.
Ref 20 ClinicalTrials.gov (NCT04365218) A Phase I Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety and Pharmacokinetics of MEDI8367 Administered as Single Ascending Doses in Healthy Subjects, and as a Single Dose in Healthy Subjects of Japanese-descent and in Subjects With Chronic Kidney Disease. U.S.National Institutes of Health.