m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0096)
Name
PARPi
Synonyms
Parpi; UNII-OWV057OPZ3; OWV057OPZ3; CHEMBL4650351; SCHEMBL19372384; 4-(4-fluoro-3-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2h)-one; 1(2H)-Phthalazinone, 4-((4-fluoro-3-((4-(4-(fluoro)benzoyl)-1-piperazinyl)carbonyl)phenyl)methyl)-; 1919043-65-4
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Status Investigative [1]
Structure
Formula
C27H22F2N4O3
InChI
InChI=1S/C27H22F2N4O3/c28-19-8-6-18(7-9-19)26(35)32-11-13-33(14-12-32)27(36)22-15-17(5-10-23(22)29)16-24-20-3-1-2-4-21(20)25(34)31-30-24/h1-10,15H,11-14,16H2,(H,31,34)
InChIKey
LTZZZXXIKHHTMO-UHFFFAOYSA-N
PubChem CID
130443213
Full List of m6A Targets Related to This Drug
Frizzled-10 (FZD10)
 Target Info 
In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Downregulation of m6A demethylases FTO and ALKBH5 was sufficient to increase Frizzled-10 (FZD10) mRNA m6A modification and reduce PARPi sensitivity, the finding elucidates a novel regulatory mechanism of PARPi resistance in EOC by showing that m6A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/Bete-catenin pathway.
Responsed Disease Malignant mixed epithelial mesenchymal tumour of ovary ICD-11: 2B5D.0
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
In-vitro Model UWB1.289 Ovarian carcinoma Homo sapiens CVCL_B079
PEO1 Ovarian cystadenocarcinoma Homo sapiens CVCL_2686
In-vivo Model 2 × 107 PARP inhibitor resistant PEO1 cells were suspended in 200 uL PBS : Matrigel (1:1) unilaterally injected subcutaneously into the right dorsal flank of 6-8 week-old female immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) gamma (NSG) mice. When the average tumor size reached ~100 mm3, the mice were then randomized into four groups and treated with vehicle control, Olaparib (50 mg/kg), XAV939 (5 mg/kg) or a combination daily for 18 days.
Experiment 2 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Downregulation of m6A demethylases FTO and ALKBH5 was sufficient to increase Frizzled-10 (FZD10) mRNA m6A modification and reduce PARPi sensitivity, the finding elucidates a novel regulatory mechanism of PARPi resistance in EOC by showing that m6A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/Bete-catenin pathway.
Responsed Disease Malignant mixed epithelial mesenchymal tumour of ovary ICD-11: 2B5D.0
 Disease Info 
Target Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
In-vitro Model UWB1.289 Ovarian carcinoma Homo sapiens CVCL_B079
PEO1 Ovarian cystadenocarcinoma Homo sapiens CVCL_2686
In-vivo Model 2 × 107 PARP inhibitor resistant PEO1 cells were suspended in 200 uL PBS : Matrigel (1:1) unilaterally injected subcutaneously into the right dorsal flank of 6-8 week-old female immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) gamma (NSG) mice. When the average tumor size reached ~100 mm3, the mice were then randomized into four groups and treated with vehicle control, Olaparib (50 mg/kg), XAV939 (5 mg/kg) or a combination daily for 18 days.
References
Ref 1 PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer. 2020 Jun 20;19(1):107. doi: 10.1186/s12943-020-01227-0.
Ref 2 N(6)-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance. Cancer Res. 2019 Jun 1;79(11):2812-2820. doi: 10.1158/0008-5472.CAN-18-3592. Epub 2019 Apr 9.