m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0066)
Name
R-2HG
Synonyms
(R)-2-Hydroxypentanedioic acid; 13095-47-1; D-2-Hydroxyglutaric acid; (R)-2-hydroxyglutaric acid; (R)-Hydroxyglutarate; (R)-2-hydroxyglutarate; Pentanedioic acid, 2-hydroxy-, (2R)-; CHEMBL1614745; CHEBI:32796; D-2-Hydroxyglutarate; Glutaric acid, 2-hydroxy-; d-alpha-hydroxyglutaric acid; D-Hydroxyglutarate; 2HG; D-a-Hydroxyglutarate; 2-hydroxy-D-Glutarate; (R)-a-Hydroxyglutarate; delta-2-Hydroxyglutarate; D-a-Hydroxyglutaric acid; 2-hydroxy-delta-Glutarate; D-; A-Hydroxyglutaric acid; (2R)-hydroxyglutaric acid; 2-hydroxy-D-Glutaric acid; (R)-alpha-Hydroxyglutarate; delta-alpha-Hydroxyglutarate; SCHEMBL8032; (R)-a-Hydroxyglutaric acid; delta-2-Hydroxyglutaric acid; (R)-2-hydroxy-Pentanedioate; 2-hydroxy-delta-Glutaric acid; (R)-alpha-Hydroxyglutaric acid; delta-alpha-Hydroxyglutaric acid; (R)-2-hydroxy-Pentanedioic acid; DTXSID80897218; ZINC402968; BDBM50361471; AKOS027325193; FD21404; BS-50252; HY-113038; CS-0059411; C01087; 93397C3E-3CE9-4FEA-A2ED-8F6FA59A1FEA; Q27104222; Z2217110365; 636-67-9
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Status Investigative [1]
Structure
Formula
C5H8O5
InChI
InChI=1S/C5H8O5/c6-3(5(9)10)1-2-4(7)8/h3,6H,1-2H2,(H,7,8)(H,9,10)/t3-/m1/s1
InChIKey
HWXBTNAVRSUOJR-GSVOUGTGSA-N
PubChem CID
439391
Full List of m6A Targets Related to This Drug
Apoptosis regulator Bcl-2 (BCL2)
 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 Studies of the aberrant expression of m6A mediators in breast cancer revealed that they were associated with different BC subtypes and functions, such as proliferation, apoptosis, stemness, the cell cycle, migration, and metastasis, through several factors and signaling pathways, such as Apoptosis regulator Bcl-2 (BCL2) and the PI3K/Akt pathway, among others. Fat mass and obesity-associated protein (FTO) was identified as the first m6A demethylase, and a series of inhibitors that target FTO were reported to have potential for the treatment of BC by inhibiting cell proliferation and promoting apoptosis.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Pathway Response Apoptosis hsa04210
PI3K-Akt signaling pathway hsa04151
Cell Process Cell proliferation
Cell apoptosis
CCAAT/enhancer-binding protein alpha (CEBPA)
 Target Info 
In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary This work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CCAAT/enhancer-binding protein alpha (CEBPA) signaling.High levels of FTO sensitize leukemia cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling.
Responsed Disease Glioma ICD-11: 2A00.0
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Cell Process Glutamine metabolism
Cell apoptosis
In-vitro Model 8-MG-BA Glioblastoma Homo sapiens CVCL_1052
A-172 Glioblastoma Homo sapiens CVCL_0131
DK-MG Glioblastoma Homo sapiens CVCL_1173
GaMG Glioblastoma Homo sapiens CVCL_1226
HEL Erythroleukemia Homo sapiens CVCL_0001
Jurkat T acute lymphoblastic leukemia Homo sapiens CVCL_0065
KOCL-45 B acute lymphoblastic leukemia Homo sapiens CVCL_3993
KOCL-48 Childhood acute monocytic leukemia Homo sapiens CVCL_6867
KOCL-50 B acute lymphoblastic leukemia Homo sapiens CVCL_6866
KOCL-51 B acute lymphoblastic leukemia Homo sapiens CVCL_6865
KOCL-69 B acute lymphoblastic leukemia Homo sapiens CVCL_3995
KOPN-1 B acute lymphoblastic leukemia Homo sapiens CVCL_3937
LN-18 Glioblastoma Homo sapiens CVCL_0392
LN-229 Glioblastoma Homo sapiens CVCL_0393
MA9.3 (MA9.3)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
MA9.6 (MLL-AF9)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
ME-1 [Human leukemia] Adult acute myeloid leukemia Homo sapiens CVCL_2110
ML-2 Adult acute myeloid leukemia Homo sapiens CVCL_1418
MV4-11 Childhood acute monocytic leukemia Homo sapiens CVCL_0064
NB4 Acute promyelocytic leukemia Homo sapiens CVCL_0005
NOMO-1 Adult acute monocytic leukemia Homo sapiens CVCL_1609
PL21 Familial adenomatous polyposis Homo sapiens CVCL_JM48
T98G Glioblastoma Homo sapiens CVCL_0556
THP-1 Childhood acute monocytic leukemia Homo sapiens CVCL_0006
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
U-937 Adult acute monocytic leukemia Homo sapiens CVCL_0007
In-vivo Model For R-2HG injection mouse models, sensitive (NOMO-1 and MA9.3ITD) or resistant (MA9.3RAS) cells were injected into NSGS or NRGS intravenously, and then R-2HG (6mg/kg body weight) or PBS were injected once daily through tail vein for 12 consecutive days starting from day 11 post xeno-transplantation.
Experiment 2 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary This work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CCAAT/enhancer-binding protein alpha (CEBPA) signaling.High levels of FTO sensitize leukemia cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling.
Responsed Disease Leukaemia ICD-11: 2B33.4
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Cell Process Glutamine metabolism
Cell apoptosis
In-vitro Model 8-MG-BA Glioblastoma Homo sapiens CVCL_1052
A-172 Glioblastoma Homo sapiens CVCL_0131
DK-MG Glioblastoma Homo sapiens CVCL_1173
GaMG Glioblastoma Homo sapiens CVCL_1226
HEL Erythroleukemia Homo sapiens CVCL_0001
Jurkat T acute lymphoblastic leukemia Homo sapiens CVCL_0065
KOCL-45 B acute lymphoblastic leukemia Homo sapiens CVCL_3993
KOCL-48 Childhood acute monocytic leukemia Homo sapiens CVCL_6867
KOCL-50 B acute lymphoblastic leukemia Homo sapiens CVCL_6866
KOCL-51 B acute lymphoblastic leukemia Homo sapiens CVCL_6865
KOCL-69 B acute lymphoblastic leukemia Homo sapiens CVCL_3995
KOPN-1 B acute lymphoblastic leukemia Homo sapiens CVCL_3937
LN-18 Glioblastoma Homo sapiens CVCL_0392
LN-229 Glioblastoma Homo sapiens CVCL_0393
MA9.3 (MA9.3)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
MA9.6 (MLL-AF9)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
ME-1 [Human leukemia] Adult acute myeloid leukemia Homo sapiens CVCL_2110
ML-2 Adult acute myeloid leukemia Homo sapiens CVCL_1418
MV4-11 Childhood acute monocytic leukemia Homo sapiens CVCL_0064
NB4 Acute promyelocytic leukemia Homo sapiens CVCL_0005
NOMO-1 Adult acute monocytic leukemia Homo sapiens CVCL_1609
PL21 Familial adenomatous polyposis Homo sapiens CVCL_JM48
T98G Glioblastoma Homo sapiens CVCL_0556
THP-1 Childhood acute monocytic leukemia Homo sapiens CVCL_0006
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
U-937 Adult acute monocytic leukemia Homo sapiens CVCL_0007
In-vivo Model For R-2HG injection mouse models, sensitive (NOMO-1 and MA9.3ITD) or resistant (MA9.3RAS) cells were injected into NSGS or NRGS intravenously, and then R-2HG (6mg/kg body weight) or PBS were injected once daily through tail vein for 12 consecutive days starting from day 11 post xeno-transplantation.
Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4)
 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 Genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4). FTO inhibitors, such as rhein, meclofenamic acid (MA), MO-I-500, fluorescein, and R-2HG, can inhibit acute myeloid leukemia cell viability. CS1 and CS2 displayed a much higher efficacy in inhibiting AML cell viability.
Responsed Disease Acute myeloid leukaemia ICD-11: 2A60
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response B cell receptor signaling pathway hsa04662
Cell Process Immune Evasion
In-vitro Model MV4-11 Childhood acute monocytic leukemia Homo sapiens CVCL_0064
THP-1 Childhood acute monocytic leukemia Homo sapiens CVCL_0006
U-937 Adult acute monocytic leukemia Homo sapiens CVCL_0007
In-vivo Model For each experiment, 6- to 8-week-old mice were used and randomly allocated to each group. For xenograft mouse, 0.1 × 106 MA9.3ITD cells were transplanted into NRGS recipient mice intravenously. Drug treatment was started from 10 days after transplantation. CS2 was administered through intraperitoneal (i.p.) injection at 5mg/kg/day, every other day. CS1 dissolved in saturated Beta-cyclodextrin (C0926, Sigma-Aldrich) solution was delivered by intravenous injection (i.v.). Successful engraftment was observed following 4 weeks post inoculation displaying a level of about 5% human CD33+ cells in peripheral. To generate PDX mouse models, 1 × 106 AML patient derived BMMNCs were transplanted into NRGS recipient mice intravenously, and drug treatment was started from 7 days later. CS2, FB23-2, and free CS1 were administered through i.p. injection at 5 mg/kg/day, while Micelle (900661, Sigma-Aldrich) packaged CS1 was delivered by i.v. injection at 5mg/kg/day. Both CS1 and CS2 were injected every other day for a total of ten times.
Myc proto-oncogene protein (MYC)
 Target Info 
In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary This work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/Myc proto-oncogene protein (MYC)/CEBPA signaling.High levels of FTO sensitize leukemia cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling.
Responsed Disease Glioma ICD-11: 2A00.0
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Cell Process Glutamine metabolism
Cell apoptosis
In-vitro Model 8-MG-BA Glioblastoma Homo sapiens CVCL_1052
A-172 Glioblastoma Homo sapiens CVCL_0131
DK-MG Glioblastoma Homo sapiens CVCL_1173
GaMG Glioblastoma Homo sapiens CVCL_1226
HEL Erythroleukemia Homo sapiens CVCL_0001
Jurkat T acute lymphoblastic leukemia Homo sapiens CVCL_0065
KOCL-45 B acute lymphoblastic leukemia Homo sapiens CVCL_3993
KOCL-48 Childhood acute monocytic leukemia Homo sapiens CVCL_6867
KOCL-50 B acute lymphoblastic leukemia Homo sapiens CVCL_6866
KOCL-51 B acute lymphoblastic leukemia Homo sapiens CVCL_6865
KOCL-69 B acute lymphoblastic leukemia Homo sapiens CVCL_3995
KOPN-1 B acute lymphoblastic leukemia Homo sapiens CVCL_3937
LN-18 Glioblastoma Homo sapiens CVCL_0392
LN-229 Glioblastoma Homo sapiens CVCL_0393
MA9.3 (MA9.3)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
MA9.6 (MLL-AF9)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
ME-1 [Human leukemia] Adult acute myeloid leukemia Homo sapiens CVCL_2110
ML-2 Adult acute myeloid leukemia Homo sapiens CVCL_1418
MV4-11 Childhood acute monocytic leukemia Homo sapiens CVCL_0064
NB4 Acute promyelocytic leukemia Homo sapiens CVCL_0005
NOMO-1 Adult acute monocytic leukemia Homo sapiens CVCL_1609
PL21 Familial adenomatous polyposis Homo sapiens CVCL_JM48
T98G Glioblastoma Homo sapiens CVCL_0556
THP-1 Childhood acute monocytic leukemia Homo sapiens CVCL_0006
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
U-937 Adult acute monocytic leukemia Homo sapiens CVCL_0007
In-vivo Model For R-2HG injection mouse models, sensitive (NOMO-1 and MA9.3ITD) or resistant (MA9.3RAS) cells were injected into NSGS or NRGS intravenously, and then R-2HG (6mg/kg body weight) or PBS were injected once daily through tail vein for 12 consecutive days starting from day 11 post xeno-transplantation.
Experiment 2 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary This work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/Myc proto-oncogene protein (MYC)/CEBPA signaling.High levels of FTO sensitize leukemia cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling.
Responsed Disease Leukaemia ICD-11: 2B33.4
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Cell Process Glutamine metabolism
Cell apoptosis
In-vitro Model 8-MG-BA Glioblastoma Homo sapiens CVCL_1052
A-172 Glioblastoma Homo sapiens CVCL_0131
DK-MG Glioblastoma Homo sapiens CVCL_1173
GaMG Glioblastoma Homo sapiens CVCL_1226
HEL Erythroleukemia Homo sapiens CVCL_0001
Jurkat T acute lymphoblastic leukemia Homo sapiens CVCL_0065
KOCL-45 B acute lymphoblastic leukemia Homo sapiens CVCL_3993
KOCL-48 Childhood acute monocytic leukemia Homo sapiens CVCL_6867
KOCL-50 B acute lymphoblastic leukemia Homo sapiens CVCL_6866
KOCL-51 B acute lymphoblastic leukemia Homo sapiens CVCL_6865
KOCL-69 B acute lymphoblastic leukemia Homo sapiens CVCL_3995
KOPN-1 B acute lymphoblastic leukemia Homo sapiens CVCL_3937
LN-18 Glioblastoma Homo sapiens CVCL_0392
LN-229 Glioblastoma Homo sapiens CVCL_0393
MA9.3 (MA9.3)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
MA9.6 (MLL-AF9)
MA9.6ITD (MLL-AF9 plus FLT3-ITD)
MA9.6RAS (MLL-AF9 plus NRasG12D)
ME-1 [Human leukemia] Adult acute myeloid leukemia Homo sapiens CVCL_2110
ML-2 Adult acute myeloid leukemia Homo sapiens CVCL_1418
MV4-11 Childhood acute monocytic leukemia Homo sapiens CVCL_0064
NB4 Acute promyelocytic leukemia Homo sapiens CVCL_0005
NOMO-1 Adult acute monocytic leukemia Homo sapiens CVCL_1609
PL21 Familial adenomatous polyposis Homo sapiens CVCL_JM48
T98G Glioblastoma Homo sapiens CVCL_0556
THP-1 Childhood acute monocytic leukemia Homo sapiens CVCL_0006
U-87MG ATCC Glioblastoma Homo sapiens CVCL_0022
U-937 Adult acute monocytic leukemia Homo sapiens CVCL_0007
In-vivo Model For R-2HG injection mouse models, sensitive (NOMO-1 and MA9.3ITD) or resistant (MA9.3RAS) cells were injected into NSGS or NRGS intravenously, and then R-2HG (6mg/kg body weight) or PBS were injected once daily through tail vein for 12 consecutive days starting from day 11 post xeno-transplantation.
References
Ref 1 R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m(6)A/PFKP/LDHB axis. Mol Cell. 2021 Mar 4;81(5):922-939.e9. doi: 10.1016/j.molcel.2020.12.026.
Ref 2 The Complex Roles and Therapeutic Implications of m(6)A Modifications in Breast Cancer. Front Cell Dev Biol. 2021 Jan 11;8:615071. doi: 10.3389/fcell.2020.615071. eCollection 2020.
Ref 3 R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling. Cell. 2018 Jan 11;172(1-2):90-105.e23. doi: 10.1016/j.cell.2017.11.031. Epub 2017 Dec 14.
Ref 4 Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion. Cancer Cell. 2020 Jul 13;38(1):79-96.e11. doi: 10.1016/j.ccell.2020.04.017. Epub 2020 Jun 11.
Ref 5 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017210)