m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0091)
Name
Tucatinib
Synonyms
Irbinitinib; Tucatinib; 937263-43-9; ONT-380; 6-DIAMINE; Tukysa; UNII-234248D0HH; N6-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-((1,2,4)triazolo(1,5-a)pyridin-7-yloxy)phenyl)quinazoline-4,6-diamine; 234248D0HH; Irbinitinib; ARRY-380; ONT-380; N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; 6-N-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-4-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine; N6-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl)-N4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamine; Irbitinib; ONT 380; Tukysa (TN); ONT-380;Tucatinib; Tucatinib (USAN/INN); Tucatinib [USAN:INN]; Irbinitinib(ARRY-380); Irbinitinib; ARRY-380; GTPL9922; SCHEMBL1193050; CHEMBL3989868; BDBM471617; BCP15983; EX-A1031; MFCD22380467; NSC764581; NSC799335; s8362; ZINC68250462; ARRY-380 (ONT-380); AKOS026750449; CCG-264747; CS-3906; DB11652; NSC-764581; NSC-799335; SB17126; US10822334, Compound ONT380; NCGC00482879-02; 4,6-Quinazolinediamine, N6-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-N4-(3-methyl-4-((1,2,4)triazolo(1,5-a)pyridin-7-yloxy)phenyl)-; AC-33037; AS-56109; BT177688; HY-16069; Example 11 [WO2007059257A2]; DB-130430; A16413; D11141; A857335; Q25100690; 4,6-QuinazolinediaMine,N6-(4,5-dihydro-4,4-diMethyl-2-oxazolyl)-N4-[3-Methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-; N6-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl)-N4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamine;; N6-(4,5-dihydro-4,4-dmethyl-2-oxazolyl)-N4-(3-methyl-4-((1,2,4)triazolo(1,5-A)pyridin-7-Yloxy)phenyl)-4,6-quinazolinediamine
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Status Approved [1]
Structure
Formula
C26H24N8O2
InChI
InChI=1S/C26H24N8O2/c1-16-10-17(5-7-22(16)36-19-8-9-34-23(12-19)28-15-30-34)31-24-20-11-18(4-6-21(20)27-14-29-24)32-25-33-26(2,3)13-35-25/h4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31)
InChIKey
SDEAXTCZPQIFQM-UHFFFAOYSA-N
PubChem CID
51039094
TTD Drug ID
D09GRX
DrugBank ID
DB11652
Full List of m6A Targets Related to This Drug
Catenin beta-1 (CTNNB1/Beta-catenin)
 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 m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates Catenin beta-1 (CTNNB1/Beta-catenin)/TCF4-SLC7A11/FPN1 signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
Cystine/glutamate transporter (SLC7A11)
 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 m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates beta-catenin/TCF4-Cystine/glutamate transporter (SLC7A11)/FPN1 signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
Fibroblast growth factor receptor 4 (FGFR4)
 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 m6A-hypomethylation regulated Fibroblast growth factor receptor 4 (FGFR4) phosphorylates GSK-3beta and activates beta-catenin/TCF4-SLC7A11/FPN1 signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
Glycogen synthase kinase-3 beta (GSK3Beta/GSK3B)
 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 m6A-hypomethylation regulated FGFR4 phosphorylates Glycogen synthase kinase-3 beta (GSK3Beta/GSK3B) and activates beta-catenin/TCF4-SLC7A11/FPN1 signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
Solute carrier family 40 member 1 (FPN1)
 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 m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3beta and activates beta-catenin/TCF4-SLC7A11/Solute carrier family 40 member 1 (FPN1) signaling to drive anti-HER2 resistance. Knockdown of METTL14 significantly increased the expression level of FGFR4 in HER2-positive breast cancer cells. FGFR4 reduced the sensitivity of HER2-positive breast cancer to trastuzumab plus pertuzumab or tucatinib. These results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
Responsed Disease Breast cancer ICD-11: 2C60
 Disease Info 
Target Regulator Methyltransferase-like 14 (METTL14) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Glutathione synthesis
In-vitro Model ZR-75-1 Invasive breast carcinoma Homo sapiens CVCL_0588
T-47D Invasive breast carcinoma Homo sapiens CVCL_0553
SUM-159 (A mesenchymal triple-negative breast cancer cell line)
SK-BR-3 Breast adenocarcinoma Homo sapiens CVCL_0033
MDA-MB-468 Breast adenocarcinoma Homo sapiens CVCL_0419
MDA-MB-453 Breast adenocarcinoma Homo sapiens CVCL_0418
MDA-MB-361 Breast adenocarcinoma Homo sapiens CVCL_0620
MDA-MB-231 Breast adenocarcinoma Homo sapiens CVCL_0062
MCF-7 Invasive breast carcinoma Homo sapiens CVCL_0031
MCF-10A Normal Homo sapiens CVCL_0598
HEK293T Normal Homo sapiens CVCL_0063
BT-549 Invasive breast carcinoma Homo sapiens CVCL_1092
BT-474 Invasive breast carcinoma Homo sapiens CVCL_0179
AU565 Breast adenocarcinoma Homo sapiens CVCL_1074
In-vivo Model Luciferase-labeled rSKBR3 and MDA-MB-361 cells (1 × 107 cells) mixed with 1:1 Matrigel (Corning, 356237) were subcutaneously injected into the fat pads of mice. After a tumor was palpable, the mice were randomized into four groups (five mice per group), and they were treated with vehicle, trastuzumab (20 mg/kg, intraperitoneal administration), roblitinib (30 mg/kg, oral administration), or a combination of both drugs.
References
Ref 1 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
Ref 2 N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun. 2022 May 13;13(1):2672. doi: 10.1038/s41467-022-30217-7.