m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0010)
Name
Temozolomide
Synonyms
Methazolastone; Temodal; Temodar; Temozolamide; Temozolodida; Temozolomidum; Essex brand of temozolomide; Scheringbrand of temozolomide; Temozolodida [Spanish]; Temozolomidum [Latin]; M B 39831; MB 39831; Sch 52365; M & B 39831; M&B 39831; M-39831; Sch-52365; Schering-Plough brand of temozolomide; TMZ-Bioshuttle; Temodal (TN); Temodar (TN); Temozolomide [INN:BAN]; M&B-39831; Temozolomide (JAN/USAN/INN); 3,4-Dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide; 3,4-Dihydro-3-methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide; 3-Methyl-4-oxo-3,4-dihydroimidazo(5,1-d)(1,2,3,5)tetrazine-8-carboxamide; 3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carboxamide; 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide; 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide; 8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one; TMZ
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Status Approved [1]
Structure
Formula
C6H6N6O2
InChI
InChI=1S/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13)
InChIKey
BPEGJWRSRHCHSN-UHFFFAOYSA-N
PubChem CID
5394
TTD Drug ID
D0C8EU
DrugBank ID
DB00853
Full List of m6A Targets Related to This Drug
DNA-3-methyladenine glycosylase (ANPG/MPG)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Two critical DNA repair genes (MGMT and DNA-3-methyladenine glycosylase (ANPG/MPG)) were m6A-modified by METTL3, whereas inhibited by METTL3 silencing or DAA-mediated total methylation inhibition, which is crucial for METTL3-improved temozolomide resistance in glioblastoma cells.
Responsed Disease Glioblastoma ICD-11: 2A00.00
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Nucleotide excision repair hsa03420
Cell Process DNA repair
In-vitro Model U251 (Fibroblasts or fibroblast like cells)
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
In-vivo Model Subcutaneously injected shMETTL3 or shNC-expressing U87-MG-TMZ cells into BALB/c NOD mice. After confirmation of GBM implantation, mice were treated with TMZ (66 mg/kg/d, 5 d per week, for 3 cycles).
Ephrin type-B receptor 3 (EPHB3)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary YTHDF2 enhanced TMZ resistance in GBM by activation of the PI3K/Akt and NF-Kappa-B signalling pathways via inhibition of Ephrin type-B receptor 3 (EPHB3) and TNFAIP3.
Responsed Disease Glioblastoma ICD-11: 2A00.00
 Disease Info 
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
Target Regulation Down regulation
Pathway Response PI3K-Akt signaling pathway hsa04151
Cell Process RNA stability
In-vitro Model T98G Glioblastoma Homo sapiens CVCL_0556
LN-229 Glioblastoma Homo sapiens CVCL_0393
In-vivo Model 5 × 106 infected T98G cells (LV-NC or LV-YTHDF2) were injected into the flanks of mice through subcutaneous.
Histone-lysine N-methyltransferase EZH2 (EZH2)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [4]
Response Summary Uncover the fundamental mechanisms underlying the interplay of m6 A RNA modification and histone modification in Temozolomide resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ-resistant glioblastoma.
Responsed Disease Glioblastoma ICD-11: 2A00.00
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Pathway Response RNA degradation hsa03018
Cell Process mRNA decay
In-vitro Model U251 (Fibroblasts or fibroblast like cells)
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
In-vivo Model Used to inject 10 uL of the U87 MG-TMZ_R-luc cell suspension in the striatum at a depth of 3 mm from the dural surface. One week after the injection of the tumor cells, 40 mg/kg/day of TMZ in saline was administered for over 2 weeks by intraperitoneal injection.
Homeobox protein NANOG (NANOG)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [5]
Response Summary In glioma, hsa_circ_0072083 could regulate Homeobox protein NANOG (NANOG) and ALKBH5 via targeting miR-1252-5p to control temozolomide resistance. circ_0072083 silence reduced NANOG expression via blocking ALKBH5-mediated demethylation.
Responsed Disease Glioma ICD-11: 2A00.0
 Disease Info 
Target Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
Target Regulation Up regulation
Cell Process Cellular Processes
Cell growth and death
Cell apoptosis
In-vitro Model HEK293T Normal Homo sapiens CVCL_0063
U251 (Fibroblasts or fibroblast like cells)
U87 (A primary glioblastoma cell line)
In-vivo Model U251/TR cells (2 × 106 per mouse) with stable transfection of sh-circ_0072083 or sh-NC were subcutaneously injected into mice.
Methylated-DNA--protein-cysteine methyltransferase (MGMT)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Two critical DNA repair genes (Methylated-DNA--protein-cysteine methyltransferase (MGMT) and APNG) were m6A-modified by METTL3, whereas inhibited by METTL3 silencing or DAA-mediated total methylation inhibition, which is crucial for METTL3-improved temozolomide resistance in glioblastoma cells.
Responsed Disease Glioblastoma ICD-11: 2A00.00
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Nucleotide excision repair hsa03420
Cell Process DNA repair
In-vitro Model U251 (Fibroblasts or fibroblast like cells)
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
In-vivo Model Subcutaneously injected shMETTL3 or shNC-expressing U87-MG-TMZ cells into BALB/c NOD mice. After confirmation of GBM implantation, mice were treated with TMZ (66 mg/kg/d, 5 d per week, for 3 cycles).
PDH kinase 1 (PDK1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [6]
Response Summary Long noncoding RNA just proximal to X-inactive specific transcript facilitates aerobic glycolysis and temozolomide chemoresistance by promoting stability of PDH kinase 1 (PDK1) mRNA in an m6A-dependent manner in glioblastoma multiforme cells. JPX interacted with N6-methyladenosine (m6A) demethylase FTO alpha-ketoglutarate dependent dioxygenase (FTO) and enhanced FTO-mediated PDK1 mRNA demethylation.
Responsed Disease Glioblastoma ICD-11: 2A00.00
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Citrate cycle hsa00020
Central carbon metabolism in cancer hsa05230
Cell Process Aerobic glycolysis
Cell apoptosis
In-vitro Model LN-18 Glioblastoma Homo sapiens CVCL_0392
LN-229 Glioblastoma Homo sapiens CVCL_0393
SHG-44 Astrocytoma Homo sapiens CVCL_6728
U251 (Fibroblasts or fibroblast like cells)
U87 (A primary glioblastoma cell line)
Receptor tyrosine-protein kinase erbB-2 (ERBB2)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [7]
Response Summary IGF2BP2 activates the expression of Receptor tyrosine-protein kinase erbB-2 (ERBB2) by recognizing the m6A of YAP, thus affecting the cell cycle of colorectal cancer, inhibiting cell apoptosis, and promoting proliferation.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) READER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Hippo signaling pathway hsa04390
Cell Process Cell apoptosis
In-vitro Model HCT 8 Colon adenocarcinoma Homo sapiens CVCL_2478
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 Colon adenocarcinoma Homo sapiens CVCL_0547
In-vivo Model IGF2BP2 activates the expression of ErbB2 by recognizing the m6A of YAP, thus affecting the cell cycle of CRC, inhibiting cell apoptosis, and promoting proliferation.
TNF alpha-induced protein 3 (TNFAIP3)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary YTHDF2 enhanced TMZ resistance in GBM by activation of the PI3K/Akt and NF-Kappa-B signalling pathways via inhibition of EPHB3 and TNF alpha-induced protein 3 (TNFAIP3).
Responsed Disease Glioblastoma ICD-11: 2A00.00
 Disease Info 
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
Target Regulation Down regulation
Pathway Response PI3K-Akt signaling pathway hsa04151
Cell Process RNA stability
In-vitro Model T98G Glioblastoma Homo sapiens CVCL_0556
LN-229 Glioblastoma Homo sapiens CVCL_0393
In-vivo Model 5 × 106 infected T98G cells (LV-NC or LV-YTHDF2) were injected into the flanks of mice through subcutaneous.
Transcriptional coactivator YAP1 (YAP1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [7]
Response Summary IGF2BP2 activates the expression of ErbB2 by recognizing the m6A of Transcriptional coactivator YAP1 (YAP1), thus affecting the cell cycle of colorectal cancer, inhibiting cell apoptosis, and promoting proliferation.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) READER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Hippo signaling pathway hsa04390
Cell Process Cell apoptosis
In-vitro Model HCT 8 Colon adenocarcinoma Homo sapiens CVCL_2478
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
SW620 Colon adenocarcinoma Homo sapiens CVCL_0547
In-vivo Model IGF2BP2 activates the expression of ErbB2 by recognizing the m6A of YAP, thus affecting the cell cycle of CRC, inhibiting cell apoptosis, and promoting proliferation.
microRNA 155 (MIR155)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [8]
Response Summary FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-microRNA 155 (MIR155)/miR-23a Cluster-MXI1 Feedback Circuit in Glioma.
Responsed Disease Glioma ICD-11: 2A00.0
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
In-vitro Model A-172 Glioblastoma Homo sapiens CVCL_0131
HEK293T Normal Homo sapiens CVCL_0063
U251 (Fibroblasts or fibroblast like cells)
U87 (A primary glioblastoma cell line)
In-vivo Model Previously prepared U87 cells (5 × 106 cells, 60 uL) stably infected with miRNA were injected subcutaneously in the right flank of the mice, whereas control U87 cells infected with empty vector were injected in the left flank.
microRNA 23a (MIR23A)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [8]
Response Summary FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/microRNA 23a (MIR23A) Cluster-MXI1 Feedback Circuit in Glioma.
Responsed Disease Glioma ICD-11: 2A00.0
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
In-vitro Model A-172 Glioblastoma Homo sapiens CVCL_0131
HEK293T Normal Homo sapiens CVCL_0063
U251 (Fibroblasts or fibroblast like cells)
U87 (A primary glioblastoma cell line)
In-vivo Model Previously prepared U87 cells (5 × 106 cells, 60 uL) stably infected with miRNA were injected subcutaneously in the right flank of the mice, whereas control U87 cells infected with empty vector were injected in the left flank.
Full List of Crosstalk(s) between m6A Modification and Epigenetic Regulation Related to This Drug
In total 13 item(s) under this drug
Crosstalk ID: M6ACROT03038
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target Histone-lysine N-methyltransferase EZH2 (EZH2)
 Target Gene 
Epigenetic Regulator Histone-lysine N-methyltransferase EZH2 (EZH2)
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac)
Crosstalk relationship m6A → Histone modification
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT03039
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target Histone-lysine N-methyltransferase EZH2 (EZH2)
 Target Gene 
Epigenetic Regulator Histone-lysine N-methyltransferase EZH2 (EZH2)
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac)
Crosstalk relationship Histone modification → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT03297
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target Methylated-DNA--protein-cysteine methyltransferase (MGMT)
 Target Gene 
Epigenetic Regulator Histone-lysine N-methyltransferase EZH2 (EZH2)
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac)
Crosstalk relationship Histone modification → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT03298
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target DNA-3-methyladenine glycosylase (ANPG/MPG)
 Target Gene 
Epigenetic Regulator Histone-lysine N-methyltransferase EZH2 (EZH2)
Regulated Target Histone H3 lysine 27 acetylation (H3K27ac)
Crosstalk relationship Histone modification → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT03325
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target Oxidized low-density lipoprotein receptor 1 (OLR1)
 Target Gene 
Epigenetic Regulator Probable JmjC domain-containing histone demethylation protein 2C (JMJD1C)
Regulated Target Histone H3 lysine 9 monomethylation (H3K9me1)
Crosstalk relationship Histone modification → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT03326
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target Guanine nucleotide-binding protein G (GNAO1)
 Target Gene 
Epigenetic Regulator Probable JmjC domain-containing histone demethylation protein 2C (JMJD1C)
Regulated Target Histone H3 lysine 9 monomethylation (H3K9me1)
Crosstalk relationship Histone modification → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT05007
 Crosstalk Info 
m6A Regulator Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)
 Regulator Info 
m6A Target E3 ubiquitin-protein ligase ZNRF3 (ZNRF3)
 Target Gene 
Epigenetic Regulator RMRP
Regulated Target Insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3)
Crosstalk relationship ncRNA → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT05358
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target Oxidized low-density lipoprotein receptor 1 (OLR1)
 Target Gene 
Epigenetic Regulator Circ_TTLL13
Regulated Target Methyltransferase-like protein 3 (METTL3)
Crosstalk relationship ncRNA → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT05359
 Crosstalk Info 
m6A Regulator YTH domain-containing family protein 1 (YTHDF1)
 Regulator Info 
m6A Target Oxidized low-density lipoprotein receptor 1 (OLR1)
 Target Gene 
Epigenetic Regulator Circ_TTLL13
Regulated Target YTH domain-containing family protein 1 (YTHDF1)
Crosstalk relationship ncRNA → m6A
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT05437
 Crosstalk Info 
m6A Regulator Fat mass and obesity-associated protein (FTO)
 Regulator Info 
m6A Target Myc proto-oncogene protein (MYC)
 Target Gene 
Epigenetic Regulator MicroRNA 23a (MIR23A)
Regulated Target Max-interacting protein 1 (MXI1)
Crosstalk relationship m6A → ncRNA
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT05438
 Crosstalk Info 
m6A Regulator Fat mass and obesity-associated protein (FTO)
 Regulator Info 
m6A Target Myc proto-oncogene protein (MYC)
 Target Gene 
Epigenetic Regulator MicroRNA 155 (MIR155)
Regulated Target Max-interacting protein 1 (MXI1)
Crosstalk relationship m6A → ncRNA
Disease Brain cancer
 Disease Info 
Crosstalk ID: M6ACROT05886
 Crosstalk Info 
m6A Regulator RNA demethylase ALKBH5 (ALKBH5)
 Regulator Info 
m6A Target Transcription factor SOX-2 (SOX2)
 Target Gene 
Epigenetic Regulator SOX2 overlapping transcript (SOX2OT)
Regulated Target RNA demethylase ALKBH5 (ALKBH5)
Crosstalk relationship ncRNA → m6A
Disease Glioblastoma
 Disease Info 
Crosstalk ID: M6ACROT05968
 Crosstalk Info 
m6A Regulator Fat mass and obesity-associated protein (FTO)
 Regulator Info 
m6A Target PDH kinase 1 (PDK1)
 Target Gene 
Epigenetic Regulator Long non-coding RNA just proximal to the X-inactive specific transcript (JPX)
Regulated Target FTO alpha-ketoglutarate dependent dioxygenase (FTO)
Crosstalk relationship ncRNA → m6A
Disease Glioblastoma multiforme
 Disease Info 
References
Ref 1 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: 7301).
Ref 2 METTL3 Promotes the Resistance of Glioma to Temozolomide via Increasing MGMT and ANPG in a m(6)A Dependent Manner. Front Oncol. 2021 Jul 15;11:702983. doi: 10.3389/fonc.2021.702983. eCollection 2021.
Ref 3 YTHDF2 promotes temozolomide resistance in glioblastoma by activation of the Akt and NF-KappaB signalling pathways via inhibiting EPHB3 and TNFAIP3. Clin Transl Immunology. 2022 May 9;11(5):e1393. doi: 10.1002/cti2.1393. eCollection 2022.
Ref 4 Interplay of m(6) A and histone modifications contributes to temozolomide resistance in glioblastoma. Clin Transl Med. 2021 Sep;11(9):e553. doi: 10.1002/ctm2.553.
Ref 5 Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma. J Exp Clin Cancer Res. 2021 May 11;40(1):164. doi: 10.1186/s13046-021-01942-6.
Ref 6 Long noncoding RNA just proximal to X-inactive specific transcript facilitates aerobic glycolysis and temozolomide chemoresistance by promoting stability of PDK1 mRNA in an m6A-dependent manner in glioblastoma multiforme cells. Cancer Sci. 2021 Nov;112(11):4543-4552. doi: 10.1111/cas.15072. Epub 2021 Aug 30.
Ref 7 IGF2BP2 promotes the progression of colorectal cancer through a YAP-dependent mechanism. Cancer Sci. 2021 Oct;112(10):4087-4099. doi: 10.1111/cas.15083. Epub 2021 Aug 3.
Ref 8 FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/23a Cluster-MXI1 Feedback Circuit in Glioma. Cancer Res. 2020 Sep 15;80(18):3945-3958. doi: 10.1158/0008-5472.CAN-20-0132. Epub 2020 Jul 17.
Ref 9 Clinical pipeline report, company report or official report of Turning Point Therapeutics.
Ref 10 The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human blood-brain barrier: evidence for involvement of breast cancer resistance protein. Brain Res. 2012 Feb 3;1436:111-21.
Ref 11 The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85. doi: 10.1016/j.bmcl.2012.06.029. Epub 2012 Jun 16.