Details of the Drug Combination

General Information of Drug Combination (ID: DCWCZTG)

• Drug Combination Name: Plinabulin + Triptolide
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Plinabulin (DMD7L48): Small molecular drug
  Triptolide (DMCMDVR): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 5.812
  Bliss Independence Score: 5.564
  Loewe Additivity Score: 0.016
  LHighest Single Agent (HSA) Score: 3.801

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Plinabulin

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

Plinabulin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Modulator	[4]
Guanine nucleotide exchange factor (GNEF)	TTKIGZF	EI2BA_HUMAN; EI2BB_HUMAN	Stimulator	[2]

Indication(s) of Triptolide

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

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]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] ClinicalTrials.gov (NCT02115659) Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD). U.S. National Institutes of Health.
• [4] NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs. 2006 Jan;17(1):25-31.
• [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.