Details of the Drug Combination

General Information of Drug Combination (ID: DCYINTX)

• Drug Combination Name: Vismodegib + Pomalidomide
• Indication: Ovarian serous cystadenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Vismodegib (DM5IXKQ): Small molecular drug
  Pomalidomide (DMTGBAX): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SK-OV-3
  Zero Interaction Potency (ZIP) Score: 0.38
  Bliss Independence Score: 8.12
  Loewe Additivity Score: 6.51
  LHighest Single Agent (HSA) Score: 7.49

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vismodegib

Disease Entry	ICD 11	Status	REF
Basal cell carcinoma	2C32	Approved	[2]
Primitive neuroectodermal tumour medulloblastoma	2A00.11	Phase 2	[3]

Vismodegib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Smoothened homolog (SMO)	TT8J1S3	SMO_HUMAN	Modulator	[6]

Vismodegib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[7]

Vismodegib Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[8]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[8]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Decreases Expression	[8]
Zinc finger protein GLI2 (GLI2)	OTIRV97L	GLI2_HUMAN	Decreases Expression	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[8]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[8]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[8]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[8]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Decreases Expression	[8]
Protein patched homolog 2 (PTCH2)	OTOQ0K9V	PTC2_HUMAN	Decreases Expression	[8]
Suppressor of fused homolog (SUFU)	OT0IRYG1	SUFU_HUMAN	Decreases Response To Substance	[9]
N-myc proto-oncogene protein (MYCN)	OTWD33K1	MYCN_HUMAN	Decreases Response To Substance	[9]

Indication(s) of Pomalidomide

Disease Entry	ICD 11	Status	REF
Plasma cell myeloma	2A83.1	Approved	[4]
Systemic sclerosis	4A42	Approved	[5]

Pomalidomide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiogenesis/myeloma cell growth (AMCG)	TTDIBYJ	NOUNIPROTAC	Modulator	[10]

Pomalidomide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]

Pomalidomide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[13]

Pomalidomide Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Oxidation	[14]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[15]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Secretion	[15]
Granulocyte colony-stimulating factor (CSF3)	OT9GC6TP	CSF3_HUMAN	Increases Secretion	[15]
Fibroblast growth factor receptor 1 (FGFR1)	OT4GLCXW	FGFR1_HUMAN	Decreases Expression	[16]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[15]
Erythroid transcription factor (GATA1)	OTX1R7O1	GATA1_HUMAN	Decreases Expression	[15]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Decreases Expression	[15]
Transcription factor PU.1 (SPI1)	OTVCA1D0	SPI1_HUMAN	Increases Expression	[15]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[15]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Affects Expression	[16]
Endothelial transcription factor GATA-2 (GATA2)	OTBP2QQ2	GATA2_HUMAN	Decreases Expression	[15]
Rhombotin-2 (LMO2)	OTCC370G	RBTN2_HUMAN	Decreases Expression	[15]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Decreases Secretion	[15]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[15]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[15]
CCAAT/enhancer-binding protein delta (CEBPD)	OTNBIPMY	CEBPD_HUMAN	Increases Expression	[15]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[15]
Krueppel-like factor 1 (KLF1)	OT1FK08U	KLF1_HUMAN	Decreases Expression	[15]
CCAAT/enhancer-binding protein epsilon (CEBPE)	OTKZA25M	CEBPE_HUMAN	Increases Expression	[15]
Transcription factor NF-E2 45 kDa subunit (NFE2)	OTLM94BI	NFE2_HUMAN	Decreases Expression	[15]
Zinc finger protein Gfi-1b (GFI1B)	OTRDW8YO	GFI1B_HUMAN	Decreases Expression	[15]
Zinc finger protein Gfi-1 (GFI1)	OT9HB9H8	GFI1_HUMAN	Increases Expression	[15]
Sal-like protein 4 (SALL4)	OTC08PR5	SALL4_HUMAN	Affects Binding	[17]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Oxidation	[14]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Increases Oxidation	[14]
Protein cereblon (CRBN)	OTXH9MDC	CRBN_HUMAN	Increases Response To Substance	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Carcinoma	DCO7MTB	MCF7	Investigative	[19]
Invasive ductal carcinoma	DCXR1TS	HS 578T	Investigative	[19]
Invasive ductal carcinoma	DC9G3X7	BT-549	Investigative	[19]
Adenocarcinoma	DCVTCLO	DU-145	Investigative	[1]
Adenocarcinoma	DCN5MRE	HCC-2998	Investigative	[1]
Adult acute myeloid leukemia	DCFNTZB	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCEV29H	MOLT-4	Investigative	[1]
Amelanotic melanoma	DCK7LN7	MDA-MB-435	Investigative	[1]
Amelanotic melanoma	DCAXEVF	M14	Investigative	[1]
Astrocytoma	DC54E06	U251	Investigative	[1]
Astrocytoma	DCWGK0V	SNB-19	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCZJHTE	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DCBVLX5	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DC7PIKD	A498	Investigative	[1]
Clear cell renal cell carcinoma	DCXKNXP	786-0	Investigative	[1]
Cutaneous melanoma	DCTOH9O	SK-MEL-28	Investigative	[1]
Glioblastoma	DCFLVNZ	SNB-75	Investigative	[1]
Glioma	DCOLHQ3	SF-539	Investigative	[1]
Glioma	DC782Y7	SF-268	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC3IA4I	OVCAR-4	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCW3Z9Z	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCEEOZN	NCI\\/ADR-RES	Investigative	[1]
Melanoma	DCS08D3	SK-MEL-2	Investigative	[1]
Melanoma	DC6MH2X	UACC-257	Investigative	[1]
Minimally invasive lung adenocarcinoma	DC55O9K	NCI-H322M	Investigative	[1]
Non-small cell lung carcinoma	DC3I1US	HOP-92	Investigative	[1]
Papillary renal cell carcinoma	DCFM1J3	ACHN	Investigative	[1]
Plasma cell myeloma	DC39JDZ	RPMI-8226	Investigative	[1]
Pleural epithelioid mesothelioma	DCAYIT3	NCI-H226	Investigative	[1]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [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: 6975).
• [3] A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol. 2015 Jul;73(1):99-105.e1.
• [4] Pomalidomide FDA Label
• [5] 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: 7348).
• [6] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [7] The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7.
• [8] Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306. doi: 10.1371/journal.pone.0027306. Epub 2011 Nov 8.
• [9] Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014 Jul;20(7):732-40. doi: 10.1038/nm.3613. Epub 2014 Jun 29.
• [10] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [11] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB08910)
• [12] Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects. J Clin Pharmacol. 2015 Feb;55(2):168-78.
• [13] Population pharmacokinetics of pomalidomide. J Clin Pharmacol. 2015 May;55(5):563-72.
• [14] Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide. Chem Res Toxicol. 2014 Jan 21;27(1):147-56. doi: 10.1021/tx4004215. Epub 2013 Dec 24.
• [15] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [16] Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity. Chem Res Toxicol. 2019 Apr 15;32(4):589-602. doi: 10.1021/acs.chemrestox.8b00286. Epub 2019 Mar 15.
• [17] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [18] A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple Myeloma Patient Samples. Appl Immunohistochem Mol Morphol. 2016 Nov/Dec;24(10):695-702. doi: 10.1097/PAI.0000000000000246.
• [19] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.