InterPAD - DETAILS

osimertinib, 1421373-65-0, AZD-9291, Mereletinib, AZD9291, AZD 9291, UNII-3C06JJ0Z2O, Osimertinib [USAN], osimertinibum, 3C06JJ0Z2O, AZD-9291 FREE BASE, N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(2-{[2-(Dimethylamino)ethyl](Methyl)amino}-4-Methoxy-5-{[4-(1-Methyl-1h-Indol-3-Yl)pyrimidin-2-Yl]amino}phenyl)prop-2-Enamide, mereletinib (obsolete INN), N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide, CHEBI:90943, 2-Propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-, AZD 9291(Osimertinib), N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-2-propenamide, N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide, Mereletinib [INN], C28H33N7O2, 2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-; N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide; AZD 9291; Osimertinib; Tagrisso, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)prop-2-enamide, N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)acrylamide, OSIMERTINIB [MI], OSIMERTINIB [INN], Osimertinib (AZD9291), Osimertinib; AZD 9291, Osimertinib; AZD-9291, AZD-9291(Osimertinib)?, OSIMERTINIB [WHO-DD], GTPL7719, CHEMBL3353410, SCHEMBL14660911, AMY9161, EX-A314, L01XE35, MereletinibAZD-9291,Osimertinib, DUYJMQONPNNFPI-UHFFFAOYSA-N, DTXSID501025961, HMS3653E10, HMS3672M05, BCP08626, BDBM50029668, MFCD27988062, NSC779217, NSC781254, NSC800812, s7297, AKOS025290756, AZD-9291 , Mereletinib, CCG-264683, CS-2018, DB09330, NSC-779217, NSC-781254, NSC-800812, SB22952, NCGC00378622-03, NCGC00378622-04, NCGC00378622-10, AC-29019, AS-16943, HY-15772, 4714B, NS00073136, SW219863-1, EN300-7382438, A854509, Q21506464, N(2{[2(diMethylaMino)ethyl](Methyl)aMino}4Methoxy5{[4(1Methyl1Hindol3yl)pyriMidin2yl]aMino}phenyl)prop2enaMide;Osimertinib, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)acrylamide, N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

No.	Title	Href
1	A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress. Phytomedicine. 2020 Mar;68:153189. doi: 10.1016/j.phymed.2020.153189.	`Click`
2	Osimertinib and pterostilbene in EGFR-mutation-positive non-small cell lung cancer (NSCLC). Int J Biol Sci. 2019 Sep 7;15(12):2607-2614. doi: 10.7150/ijbs.32889.	`Click`
3	Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol. Mol Oncol. 2020 Apr;14(4):882-895. doi: 10.1002/1878-0261.12645.	`Click`
4	Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer. Mol Cancer. 2022;21(1):193. Published 2022 Oct 6. doi:10.1186/s12943-022-01662-1	`Click`
5	Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway. Am J Cancer Res. 2023;13(9):4145-4162.	`Click`
6	Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis. Phytother Res. 2023;37(12):5837-5853. doi:10.1002/ptr.7990	`Click`
7	Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer. Pharmacol Res. 2021 Aug;170:105701. doi: 10.1016/j.phrs.2021.105701.	`Click`
8	Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer. Toxicol Appl Pharmacol. 2019 Sep 15;379:114662. doi: 10.1016/j.taap.2019.114662.	`Click`

No.

Title

Href

A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress. Phytomedicine. 2020 Mar;68:153189. doi: 10.1016/j.phymed.2020.153189.

Click

Osimertinib and pterostilbene in EGFR-mutation-positive non-small cell lung cancer (NSCLC). Int J Biol Sci. 2019 Sep 7;15(12):2607-2614. doi: 10.7150/ijbs.32889.

Click

Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol. Mol Oncol. 2020 Apr;14(4):882-895. doi: 10.1002/1878-0261.12645.

Click

Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer. Mol Cancer. 2022;21(1):193. Published 2022 Oct 6. doi:10.1186/s12943-022-01662-1

Click

Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway. Am J Cancer Res. 2023;13(9):4145-4162.

Click

Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis. Phytother Res. 2023;37(12):5837-5853. doi:10.1002/ptr.7990

Click

Dihydroartemisinin overcomes the resistance to osimertinib in EGFR-mutant non-small-cell lung cancer. Pharmacol Res. 2021 Aug;170:105701. doi: 10.1016/j.phrs.2021.105701.

Click

Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer. Toxicol Appl Pharmacol. 2019 Sep 15;379:114662. doi: 10.1016/j.taap.2019.114662.

Click

Name	Osimertinib
PubChem CID	71496458
Molecular Weight	499.6g/mol
Synonyms	osimertinib, 1421373-65-0, AZD-9291, Mereletinib, AZD9291, AZD 9291, UNII-3C06JJ0Z2O, Osimertinib [USAN], osimertinibum, 3C06JJ0Z2O, AZD-9291 FREE BASE, N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(2-{[2-(Dimethylamino)ethyl](Methyl)amino}-4-Methoxy-5-{[4-(1-Methyl-1h-Indol-3-Yl)pyrimidin-2-Yl]amino}phenyl)prop-2-Enamide, mereletinib (obsolete INN), N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide, CHEBI:90943, 2-Propenamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-, AZD 9291(Osimertinib), N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide, N-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-2-propenamide, N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide, Mereletinib [INN], C28H33N7O2, 2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-; N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide; AZD 9291; Osimertinib; Tagrisso, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)prop-2-enamide, N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)acrylamide, OSIMERTINIB [MI], OSIMERTINIB [INN], Osimertinib (AZD9291), Osimertinib; AZD 9291, Osimertinib; AZD-9291, AZD-9291(Osimertinib)?, OSIMERTINIB [WHO-DD], GTPL7719, CHEMBL3353410, SCHEMBL14660911, AMY9161, EX-A314, L01XE35, MereletinibAZD-9291,Osimertinib, DUYJMQONPNNFPI-UHFFFAOYSA-N, DTXSID501025961, HMS3653E10, HMS3672M05, BCP08626, BDBM50029668, MFCD27988062, NSC779217, NSC781254, NSC800812, s7297, AKOS025290756, AZD-9291 , Mereletinib, CCG-264683, CS-2018, DB09330, NSC-779217, NSC-781254, NSC-800812, SB22952, NCGC00378622-03, NCGC00378622-04, NCGC00378622-10, AC-29019, AS-16943, HY-15772, 4714B, NS00073136, SW219863-1, EN300-7382438, A854509, Q21506464, N(2{[2(diMethylaMino)ethyl](Methyl)aMino}4Methoxy5{[4(1Methyl1Hindol3yl)pyriMidin2yl]aMino}phenyl)prop2enaMide;Osimertinib, N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)acrylamide, N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
Drug Type	Small molecule
Formula	C₂₈H₃₃N₇O₂
SMILES	CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC
InChI	1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)
InChIKey	DUYJMQONPNNFPI-UHFFFAOYSA-N
CAS Number	1421373-65-0
ChEMBL ID	CHEMBL3353410
ChEBI ID	CHEBI:90943
TTD ID	D0O8GK
Drug Bank ID	DB09330
Toxicity	Organism	Test Type	Route(Dose)
	rat	LD50	intraperitoneal(165 mg/kg)
	mouse	LD50	intraperitoneal(254 mg/kg)
	rat	LD50	oral(322 mg/kg)
Structure			Download 2D MOL 3D MOL

Pair Name	Shikonin, Osimertinib
Partner Name	Shikonin
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	InductionROS generation
Gene Regulation	Up-regulation	Expression	ATF4	hsa468
Gene Regulation	Up-regulation	Phosphorylation	EIF2S1	hsa1965
In Vitro Model	A-549	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_0023
	NCI-H1299	Lung large cell carcinoma	Homo sapiens (Human)	CVCL_0060
	NCI-H460	Lung large cell carcinoma	Homo sapiens (Human)	CVCL_0459
Result	Shikonin increased the anticancer activity of AZD9291 in primary wtEGFR NSCLC cells through ROS-mediated ER stress

Pair Name	Pterostilbene, Osimertinib
Partner Name	Pterostilbene
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Gene Regulation	Down-regulation	Phosphorylation	CDCP1	hsa64866
	Down-regulation	Phosphorylation	STAT3	hsa6774
	Down-regulation	Phosphorylation	YAP1	hsa10413
In Vitro Model	MDA-MB-231	Breast adenocarcinoma	Homo sapiens (Human)	CVCL_0062
	PC-9	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_B260
	NCI-H1975	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_1511
Result	The results of this study indicate that pterostilbene may be used to abrogate the activated resistance pathways of single osimertinib treatment in EGFR-mutation positive NSCLC. Future studies should focus on in vivo translation and confirmation of these results.

Pair Name	Honokiol, Osimertinib
Partner Name	Honokiol
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	Induction-->Apoptosis
Gene Regulation	Down-regulation	Expression	MCL1	hsa4170
In Vitro Model	PC-9	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_B260
	PC-9-GR-high	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_S706
	HCC827	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_2063
	NCI-H1975/OSIR	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_WV99
In Vivo Model	The treatments included vehicle control, Osim (10 mg/kg/day, 5 days/week, og), HNK (50 mg/kg/day; ip), and their combination.
Result	Our findings warrant further study of HNK and its derivatives in overcoming Osim resistance in the clinic.

Pair Name	Costunolide, Osimertinib
Partner Name	Costunolide
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	Induction-->Apoptosis
Gene Regulation	Down-regulation	Phosphorylation	AKT1	hsa207
	Down-regulation	Phosphorylation	GSK3B	hsa2932
	Down-regulation	Phosphorylation	MAP2K1	KEGG ID N.A.
	Down-regulation	Phosphorylation	MAPK1	hsa5594
	Down-regulation	Phosphorylation	NFKB1	hsa4790
	Down-regulation	Phosphorylation	RPS6KA3	KEGG ID N.A.
In Vitro Model	PC-9	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_B260
	HCC827	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_2063
	NCI-H1975	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_1511
In Vivo Model	6–7 weeks old female mice with severe combined immunodeficiency (SCID) were employed to eatablish osimertinib-resistant PDX model.
Result	The combination of osimertinib and costunolide showed synergistic or additive inhibitory effects on tumor growth in osimertinib-resistant cell lines and PDX model. Hence, this study highlights a potential therapeutic strategy for osimertinib-resistant patients through targeting of MEK1 and AKT1/2 by costunolide.

Pair Name	Luteolin, Osimertinib
Partner Name	Luteolin
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	Inhibition-->Epithelial-mesenchymal transition
Gene Regulation	Down-regulation	Phosphorylation	AKT1	hsa207
	Down-regulation	Expression	HGF	hsa3082
	Down-regulation	Phosphorylation	MET	hsa4233
In Vitro Model	NCI-H1975	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_1511
Result	Luteolin can synergize with osimertinib to overcome MET amplification and overactivation-induced acquired resistance to osimertinib by suppressing the HGF-MET-Akt pathway, suggesting the clinical potential of combining luteolin with osimertinib in NSCLC patients with acquired resistance.

Pair Name	Epigallocatechin gallate, Osimertinib
Partner Name	Epigallocatechin gallate
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	Inhibition-->Glycolysis
Gene Regulation	Down-regulation	Phosphorylation	AKT1	hsa207
	Down-regulation	Phosphorylation	MAPK1	hsa5594
	Down-regulation	Phosphorylation	MTOR	hsa2475
	Up-regulation	Activity	PRKAA1	hsa5562
	Up-regulation	Expression	ROS1	hsa6098
In Vitro Model	NCI-H1975	Gefitinib-resistant lung adenocarcinoma	Homo sapiens (Human)	N.A.
In Vivo Model	Human NCI-H1975 or AR cells were subcutaneously inoculated into the right flank of nude mice at a density of 2×10⁶ cells for H1975 and 5×10⁶ cells for AR, respectively. When the tumors grew to reach around 100 cm3 in volume, the animals were randomly divided into 6 groups with equal size (n = 5 mice per group) for treatment.
Result	The combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. The in vivo results obtained from mouse tumor xenograft model confirmed that EGCG effectively overcame osimertinib resistance.

Pair Name	Dihydroartemisinin, Osimertinib
Partner Name	Dihydroartemisinin
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	Induction-->ROS generation
Gene Regulation	Down-regulation	Expression	HMOX1	hsa3162
Gene Regulation	Up-regulation	Expression	ROS1	hsa6098
In Vitro Model	PC-9	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_B260
In Vitro Model	PC-9/GR4	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_DH34
In Vivo Model	PC-9 or PC9-GR4-AZD1 cells (4×10⁶ cells resuspended in 200 μl of 1:1 mixture of PBS / Corning Matrigel Basement Membrane Matrix) were injected subcutaneously into the right flank of mice.
Result	The results suggest that DHA is able to reverse the resistance to osimertinib in EGFR-mutant NSCLC by elevating ROS level and impair heme metabolism.

Pair Name	Bufalin, Osimertinib
Partner Name	Bufalin
Disease Info	[ICD-11: 2C25]	Lung cancer		Investigative
Biological Phenomena	Induction-->Apoptosis
Gene Regulation	Down-regulation	Expression	MCL1	hsa4170
In Vitro Model	HCC827	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_2063
In Vitro Model	PC-9	Lung adenocarcinoma	Homo sapiens (Human)	CVCL_B260
Result	Our study suggests that bufalin eliminates resistance to osimertinib by inhibiting Ku70-mediated MCL-1 overexpression, indicating that a combination of osimertinib and bufalin could be an effective additional treatment to overcome acquired resistance to osimertinib in NSCLC cells.