Details of the Drug Combination

General Information of Drug Combination (ID: DCU2QJA)

• Drug Combination Name: Triptolide + Osimertinib
• Indication: Advanced Lung Non-Small Cell Carcinoma; Status: Phase 1 [1]
• Component Drugs:
  Triptolide (DMCMDVR): Small molecular drug
  Osimertinib (DMRJLAT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Triptolide

Disease Entry	ICD 11	Status	REF
Autoimmune diabetes	5A10	Phase 3	[2]

Triptolide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Nuclear factor NF-kappa-B (NFKB)	TTSXVID	NFKB1_HUMAN; NFKB2_HUMAN; TF65_HUMAN; RELB_HUMAN; REL_HUMAN	Inhibitor	[6]

Triptolide Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Triptolide Interacts with 32 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Decreases Expression	[8]
Histone-lysine N-methyltransferase SUV39H1 (SUV39H1)	OTDTF5BU	SUV91_HUMAN	Decreases Expression	[9]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Expression	[8]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[10]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Expression	[11]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[12]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Decreases Expression	[13]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[10]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[5]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[10]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[8]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Expression	[14]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[10]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[10]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Decreases Expression	[15]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Affects Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[16]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[17]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Expression	[5]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[18]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[5]
Cyclin-A1 (CCNA1)	OTX4HD45	CCNA1_HUMAN	Decreases Expression	[10]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Decreases Expression	[8]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[16]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Decreases Expression	[14]
Transcription factor HES-1 (HES1)	OT8P19W2	HES1_HUMAN	Decreases Expression	[5]
Histone-lysine N-methyltransferase EZH2 (EZH2)	OTIEHTKW	EZH2_HUMAN	Decreases Expression	[9]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Expression	[14]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[8]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Expression	[12]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Decreases Response To Substance	[19]

Indication(s) of Osimertinib

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Melanoma	2C30	Phase 3	[4]

Osimertinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[22]

Osimertinib Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[23]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[24]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[21]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[25]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[26]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[26]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[23]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[24]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[27]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Response To Substance	[24]

References

• [1] ClinicalTrials.gov (NCT05166616) Minnelide and Osimertinib for the Treatment of Advanced EGFR Mutated Non-Small Cell Lung Cancer
• [2] ClinicalTrials.gov (NCT02115659) Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD). U.S. National Institutes of Health.
• [3] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [4] 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: 7719).
• [5] Triptolide impairs thioredoxin system by suppressing Notch1-mediated PTEN/Akt/Txnip signaling in hepatocytes. Toxicol Lett. 2019 Jan;300:105-115. doi: 10.1016/j.toxlet.2018.10.024. Epub 2018 Oct 28.
• [6] Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene. 2001 Nov 29;20(55):8009-18.
• [7] Preclinical pharmacokinetics of triptolide: a potential antitumor drug. Curr Drug Metab. 2019;20(2):147-154.
• [8] Variable p53/Nrf2 crosstalk contributes to triptolide-induced hepatotoxic process. Toxicol Lett. 2023 Apr 15;379:67-75. doi: 10.1016/j.toxlet.2023.03.011. Epub 2023 Mar 28.
• [9] Triptolide alters histone H3K9 and H3K27 methylation state and induces G0/G1 arrest and caspase-dependent apoptosis in multiple myeloma in vitro. Toxicology. 2010 Jan 12;267(1-3):70-9. doi: 10.1016/j.tox.2009.10.023. Epub 2009 Oct 29.
• [10] Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther. 2003 Jan;2(1):65-72.
• [11] Interleukin-6-independent expression of glucocorticoid receptor is upregulated by triptolide in multiple myeloma. Leuk Lymphoma. 2009 May;50(5):802-8. doi: 10.1080/10428190902801838.
• [12] High-content analysis boosts identification of the initial cause of triptolide-induced hepatotoxicity. J Appl Toxicol. 2019 Sep;39(9):1337-1347. doi: 10.1002/jat.3821. Epub 2019 Jun 19.
• [13] Upregulation of ICAM-1 expression in bronchial epithelial cells by airway secretions in bronchiectasis. Respir Med. 2008 Feb;102(2):287-98. doi: 10.1016/j.rmed.2007.08.013. Epub 2007 Oct 10.
• [14] Catalpol and panax notoginseng saponins synergistically alleviate triptolide-induced hepatotoxicity through Nrf2/ARE pathway. Toxicol In Vitro. 2019 Apr;56:141-149. doi: 10.1016/j.tiv.2019.01.016. Epub 2019 Jan 23.
• [15] Differential expression and oxidation of MKP-1 modulates TNF-alpha gene expression. Am J Respir Cell Mol Biol. 2007 Sep;37(3):366-74. doi: 10.1165/rcmb.2006-0268OC. Epub 2007 May 16.
• [16] [Study of triptolide-induced apoptosis in MUTZ-1 cells and its allied mechanism]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Jun;13(3):434-9.
• [17] Establishment of hypoxia induction in an in vivo animal replacement model for experimental evaluation of pancreatic cancer. Oncol Rep. 2014 Jul;32(1):153-8. doi: 10.3892/or.2014.3196. Epub 2014 May 16.
• [18] Cytotoxicity of Triptolide and Triptolide loaded polymeric micelles in vitro. Toxicol In Vitro. 2011 Dec;25(8):1557-67. doi: 10.1016/j.tiv.2011.05.020. Epub 2011 May 27.
• [19] Heat shock protein 72 protects kidney proximal tubule cells from injury induced by triptolide by means of activation of the MEK/ERK pathway. Int J Toxicol. 2009 May-Jun;28(3):177-89. doi: 10.1177/1091581809337418.
• [20] In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions. Toxicol Lett. 2021 Sep 15;348:10-17. doi: 10.1016/j.toxlet.2021.05.004. Epub 2021 May 24.
• [21] Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene. 2019 Jan;38(5):656-670. doi: 10.1038/s41388-018-0482-y. Epub 2018 Aug 31.
• [22] AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.
• [23] Dihydromyricetin suppresses tumor growth via downregulation of the EGFR/Akt/survivin signaling pathway. J Biochem Mol Toxicol. 2023 Jun;37(6):e23328. doi: 10.1002/jbt.23328. Epub 2023 Feb 19.
• [24] Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells. Toxicol Appl Pharmacol. 2017 Apr 15;321:18-26. doi: 10.1016/j.taap.2017.02.017. Epub 2017 Feb 22.
• [25] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [26] Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. Biochem Pharmacol. 2022 Jan;195:114864. doi: 10.1016/j.bcp.2021.114864. Epub 2021 Nov 30.
• [27] AZD9291 promotes autophagy and inhibits PI3K/Akt pathway in NSCLC cancer cells. J Cell Biochem. 2019 Jan;120(1):756-767. doi: 10.1002/jcb.27434. Epub 2018 Aug 26.