Details of the Drug Combination

General Information of Drug Combination (ID: DC3GYRB)

• Drug Combination Name: BIBW 2992 + DZNep
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  BIBW 2992 (DMTKD7Q): Small molecular drug
  DZNep (DM0JXBK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 28.452
  Bliss Independence Score: 30.856
  Loewe Additivity Score: 0.362
  LHighest Single Agent (HSA) Score: 3.234

Molecular Interaction Atlas of This Drug Combination

Indication(s) of BIBW 2992

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

BIBW 2992 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[4]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[4]

BIBW 2992 Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[5]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[5]

BIBW 2992 Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[6]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[7]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[8]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Affects Localization	[9]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[10]
Calmodulin-1 (CALM2)	OTNYA92F	CALM1_HUMAN	Affects Response To Substance	[11]

Indication(s) of DZNep

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[3]

DZNep Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosylhomocysteinase (AHCY)	TTE2KUJ	SAHH_HUMAN	Inhibitor	[3]

DZNep Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Huntingtin-interacting protein 1 (HIP1)	OT7AKCFQ	HIP1_HUMAN	Decreases Expression	[12]
Histone-lysine N-methyltransferase SUV39H1 (SUV39H1)	OTDTF5BU	SUV91_HUMAN	Increases Expression	[12]
Histone-lysine N-methyltransferase NSD2 (NSD2)	OTQ6SW4R	NSD2_HUMAN	Increases Degradation	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[13]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Decreases Expression	[13]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[14]
Coilin (COIL)	OTP4I4DL	COIL_HUMAN	Increases Expression	[12]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[12]
Hexokinase-2 (HK2)	OTC0GCQO	HXK2_HUMAN	Decreases Expression	[13]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Increases Expression	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[13]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[13]
Histone-lysine N-methyltransferase EZH2 (EZH2)	OTIEHTKW	EZH2_HUMAN	Decreases Activity	[15]
Transcriptional protein SWT1 (SWT1)	OTY4AFM1	SWT1_HUMAN	Decreases Expression	[12]
Transmembrane protein 87A (TMEM87A)	OT8ATDVX	TM87A_HUMAN	Increases Expression	[12]
Dapper homolog 3 (DACT3)	OTSNQ55G	DACT3_HUMAN	Affects Expression	[16]
Fructose-2,6-bisphosphatase TIGAR (TIGAR)	OTR7NMRJ	TIGAR_HUMAN	Decreases Expression	[13]
E3 ubiquitin-protein ligase Jade-2 (JADE2)	OTVG2MYF	JADE2_HUMAN	Increases Expression	[12]
Kelch-like protein 42 (KLHL42)	OTK6WARI	KLH42_HUMAN	Increases Expression	[12]
Two pore channel protein 1 (TPCN1)	OTT4C4DI	TPC1_HUMAN	Decreases Expression	[12]
DmX-like protein 1 (DMXL1)	OTWVL31L	DMXL1_HUMAN	Decreases Expression	[12]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Response To Substance	[17]

References

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• [2] 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: 5667).
• [3] 3-Deazaneplanocin: a new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60. Biochem Biophys Res Commun. 1986 Mar 13;135(2):688-94.
• [4] Boehringer Ingelheim. Product Development Pipeline. June 2 2009.
• [5] Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation. Pharmacol Res. 2017 Jun;120:43-50.
• [6] Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
• [7] Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
• [8] Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. J Biol Chem. 2020 Dec 25;295(52):18105-18121. doi: 10.1074/jbc.RA120.015891. Epub 2020 Oct 21.
• [9] Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer. Cell Biol Toxicol. 2023 Aug;39(4):1795-1814. doi: 10.1007/s10565-022-09784-4. Epub 2022 Dec 19.
• [10] YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS One. 2017 Aug 7;12(8):e0182149. doi: 10.1371/journal.pone.0182149. eCollection 2017.
• [11] Knockdown of CALM2 increases the sensitivity to afatinib in HER2-amplified gastric cancer cells by regulating the Akt/FoxO3a/Puma axis. Toxicol In Vitro. 2023 Mar;87:105531. doi: 10.1016/j.tiv.2022.105531. Epub 2022 Nov 29.
• [12] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [13] S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis. Chem Biol Interact. 2020 Feb 1;317:108965. doi: 10.1016/j.cbi.2020.108965. Epub 2020 Jan 28.
• [14] Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2. Biochem Pharmacol. 2011 Feb 15;81(4):510-7. doi: 10.1016/j.bcp.2010.11.014. Epub 2010 Nov 27.
• [15] Upregulation of histone-lysine methyltransferases plays a causal role in hexavalent chromium-induced cancer stem cell-like property and cell transformation. Toxicol Appl Pharmacol. 2018 Mar 1;342:22-30. doi: 10.1016/j.taap.2018.01.022. Epub 2018 Jan 31.
• [16] DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 2008 Jun;13(6):529-41. doi: 10.1016/j.ccr.2008.04.019.
• [17] Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia. 2013 Dec;27(12):2341-50. doi: 10.1038/leu.2013.94. Epub 2013 Mar 29.