Details of the Drug Combination

General Information of Drug Combination (ID: DCDE5KD)

• Drug Combination Name: Crizotinib + Ifosfamide
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  Crizotinib (DM4F29C): Small molecular drug
  Ifosfamide (DMCT3I8): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T-47D
  Zero Interaction Potency (ZIP) Score: 4.14
  Bliss Independence Score: 6.37
  Loewe Additivity Score: 4.69
  LHighest Single Agent (HSA) Score: 4.69

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Crizotinib

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

Crizotinib Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proto-oncogene c-Met (MET)	TTNDSF4	MET_HUMAN	Modulator	[8]
ALK tyrosine kinase receptor (ALK)	TTPMQSO	ALK_HUMAN	Modulator	[8]
Proto-oncogene c-Ros (ROS1)	TTSZ6Y3	ROS1_HUMAN	Modulator	[8]
HGF/Met signaling pathway (HGF/Met pathway)	TTKA5LP	NOUNIPROTAC	Inhibitor	[9]

Crizotinib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[11]

Crizotinib 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 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]

Crizotinib Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[13]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Response To Substance	[6]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[5]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Decreases Expression	[5]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[14]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[14]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[14]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[14]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[14]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Decreases Activity	[14]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[6]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[6]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Decreases Secretion	[15]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[15]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Activity	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[17]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[18]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[19]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[20]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[6]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[13]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Response To Substance	[21]

Indication(s) of Ifosfamide

Disease Entry	ICD 11	Status	REF
Adult central nervous system germ cell tumor	N.A.	Approved	[3]
Adult teratoma	N.A.	Approved	[3]
Advanced cancer	2A00-2F9Z	Approved	[3]
Extragonadal germ cell cancer	N.A.	Approved	[3]
Extragonadal germ cell tumor	N.A.	Approved	[3]
Kidney neoplasm	N.A.	Approved	[3]
Solid tumour/cancer	2A00-2F9Z	Approved	[4]
Testicular germ cell tumor	N.A.	Approved	[3]
Extragonadal nonseminomatous germ cell tumor	N.A.	Investigative	[3]
Extragonadal seminoma	N.A.	Investigative	[3]
Neuroblastoma	2D11.2	Investigative	[3]
Retinoblastoma	2D02.2	Investigative	[3]

Ifosfamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[23]

Ifosfamide Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[24]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[25]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[26]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[27]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[28]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[26]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[29]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[30]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[28]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[24]

Ifosfamide Interacts with 153 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Response To Substance	[31]
Alpha-2A adrenergic receptor (ADRA2A)	OTZFGOTP	ADA2A_HUMAN	Increases ADR	[32]
Solute carrier family 12 member 8 (SLC12A8)	OTHJP5FU	S12A8_HUMAN	Decreases Expression	[22]
Agrin (AGRN)	OTWJENAZ	AGRIN_HUMAN	Increases Expression	[22]
Podocalyxin (PODXL)	OTPNQXF3	PODXL_HUMAN	Decreases Expression	[22]
Class E basic helix-loop-helix protein 40 (BHLHE40)	OTITX14U	BHE40_HUMAN	Increases Expression	[22]
TRAF-type zinc finger domain-containing protein 1 (TRAFD1)	OT7AU2R3	TRAD1_HUMAN	Increases Expression	[22]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[22]
Rho guanine nucleotide exchange factor 10 (ARHGEF10)	OTHJ1Y4I	ARHGA_HUMAN	Affects Expression	[22]
Apoptosis regulatory protein Siva (SIVA1)	OTDT0XZK	SIVA_HUMAN	Increases Expression	[22]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Increases Expression	[22]
E3 ubiquitin-protein ligase SIAH2 (SIAH2)	OTKED2XN	SIAH2_HUMAN	Increases Expression	[22]
Protein regulator of cytokinesis 1 (PRC1)	OTHD0XS0	PRC1_HUMAN	Increases Expression	[22]
TP53-regulated inhibitor of apoptosis 1 (TRIAP1)	OTEAUJXN	TRIA1_HUMAN	Increases Expression	[22]
5'-AMP-activated protein kinase subunit beta-2 (PRKAB2)	OTLVN68B	AAKB2_HUMAN	Affects Expression	[22]
Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20)	OT6CLFXB	MCAT_HUMAN	Increases Expression	[22]
NUAK family SNF1-like kinase 1 (NUAK1)	OTLLHJJQ	NUAK1_HUMAN	Decreases Expression	[22]
High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A (PDE8A)	OT4RF9Z4	PDE8A_HUMAN	Decreases Expression	[22]
Mitochondrial import inner membrane translocase subunit Tim17-B (TIMM17B)	OTSQGLSB	TI17B_HUMAN	Decreases Expression	[22]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[22]
E3 ubiquitin-protein ligase listerin (LTN1)	OTIW2HTX	LTN1_HUMAN	Decreases Expression	[22]
Tumor necrosis factor alpha-induced protein 8 (TNFAIP8)	OT1G9297	TFIP8_HUMAN	Increases Expression	[22]
Tetraspanin-12 (TSPAN12)	OTF9I3CX	TSN12_HUMAN	Decreases Expression	[22]
Fructose-bisphosphate aldolase A (ALDOA)	OTWRFTIB	ALDOA_HUMAN	Increases Expression	[22]
Fatty acid-binding protein, heart (FABP3)	OT562DA1	FABPH_HUMAN	Decreases Expression	[22]
Transcription factor AP-2-alpha (TFAP2A)	OTMYT3NK	AP2A_HUMAN	Decreases Expression	[22]
Glycogen phosphorylase, liver form (PYGL)	OTS1YFGR	PYGL_HUMAN	Decreases Expression	[22]
Amino acid transporter heavy chain SLC3A2 (SLC3A2)	OTBR33M9	4F2_HUMAN	Increases Expression	[22]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[22]
RNA-binding protein RO60 (RO60)	OTLGM5A8	RO60_HUMAN	Decreases Expression	[22]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Increases Expression	[22]
Cation-independent mannose-6-phosphate receptor (IGF2R)	OTDXPQVX	MPRI_HUMAN	Increases Expression	[22]
Protein SON (SON)	OT9VWV18	SON_HUMAN	Decreases Expression	[22]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Affects Activity	[22]
Keratin, type I cytoskeletal 15 (KRT15)	OTS6WLF7	K1C15_HUMAN	Increases Expression	[22]
Ephrin-A1 (EFNA1)	OTU2NUA2	EFNA1_HUMAN	Decreases Expression	[22]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Decreases Expression	[22]
Diacylglycerol kinase alpha (DGKA)	OTTBVNEZ	DGKA_HUMAN	Increases Expression	[22]
DnaJ homolog subfamily B member 2 (DNAJB2)	OTZHPV5M	DNJB2_HUMAN	Increases Expression	[22]
Threonine--tRNA ligase 1, cytoplasmic (TARS1)	OT0PWST5	SYTC_HUMAN	Decreases Expression	[22]
Adenylate kinase 4, mitochondrial (AK4)	OTA0T02Q	KAD4_HUMAN	Increases Expression	[22]
ETS domain-containing protein Elk-4 (ELK4)	OTVSSEOE	ELK4_HUMAN	Decreases Expression	[22]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Increases Expression	[22]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[22]
Pyrroline-5-carboxylate reductase 1, mitochondrial (PYCR1)	OTQHB52T	P5CR1_HUMAN	Increases Expression	[22]
Long-chain-fatty-acid--CoA ligase 1 (ACSL1)	OTB06ESI	ACSL1_HUMAN	Decreases Expression	[22]
Thrombospondin-2 (THBS2)	OTXET551	TSP2_HUMAN	Decreases Expression	[22]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[22]
Transaldolase (TALDO1)	OTDKV2S2	TALDO_HUMAN	Increases Expression	[22]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[22]
Glycine--tRNA ligase (GARS1)	OT5B6R9Y	GARS_HUMAN	Increases Expression	[22]
Isoleucine--tRNA ligase, cytoplasmic (IARS1)	OT9WXH5N	SYIC_HUMAN	Increases Expression	[22]
Tumor necrosis factor ligand superfamily member 9 (TNFSF9)	OTV9L89D	TNFL9_HUMAN	Increases Expression	[22]
Eukaryotic translation initiation factor 1 (EIF1)	OTB4GZ0V	EIF1_HUMAN	Increases Expression	[22]
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Increases Expression	[22]
Cysteine--tRNA ligase, cytoplasmic (CARS1)	OTOUZF6O	SYCC_HUMAN	Decreases Expression	[22]
Serine--tRNA ligase, cytoplasmic (SARS1)	OTFKXQ1O	SYSC_HUMAN	Increases Expression	[22]
Max-interacting protein 1 (MXI1)	OTUQ9E0D	MXI1_HUMAN	Decreases Expression	[22]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Increases Expression	[22]
Ataxin-1 (ATXN1)	OTQF0HNR	ATX1_HUMAN	Decreases Expression	[22]
Branched-chain-amino-acid aminotransferase, cytosolic (BCAT1)	OTYHXLWZ	BCAT1_HUMAN	Decreases Expression	[22]
Homeobox protein DLX-1 (DLX1)	OT7BH057	DLX1_HUMAN	Decreases Expression	[22]
Protein BTG2 (BTG2)	OTZF6K1H	BTG2_HUMAN	Increases Expression	[22]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Increases Expression	[22]
Transmembrane protein 94 (TMEM94)	OTT4ZSUA	TMM94_HUMAN	Decreases Expression	[22]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Decreases Expression	[22]
Zinc finger protein Rlf (RLF)	OTCSPZVK	RLF_HUMAN	Increases Expression	[22]
Peptidyl-prolyl cis-trans isomerase G (PPIG)	OTZ8BTTM	PPIG_HUMAN	Decreases Expression	[22]
Ras-related protein Rab-31 (RAB31)	OTMLXQZ0	RAB31_HUMAN	Increases Expression	[22]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Increases Expression	[22]
Src substrate cortactin (CTTN)	OTJRG4ES	SRC8_HUMAN	Increases Expression	[22]
Protein disulfide-isomerase A5 (PDIA5)	OT76ZSX5	PDIA5_HUMAN	Increases Expression	[22]
Condensin complex subunit 1 (NCAPD2)	OT8VGE2O	CND1_HUMAN	Increases Expression	[22]
Probable E3 ubiquitin-protein ligase HERC3 (HERC3)	OTWMKYD9	HERC3_HUMAN	Decreases Expression	[22]
kinase isozyme 1, mitochondrial (PDK1)	OTMABK9Z	PDK1_HUMAN	Decreases Expression	[22]
Neutral amino acid transporter B(0) (SLC1A5)	OTE2H26Q	AAAT_HUMAN	Increases Expression	[22]
Cyclin-G2 (CCNG2)	OTII38K2	CCNG2_HUMAN	Decreases Expression	[22]
Neuronal regeneration-related protein (NREP)	OT2AZPKK	NREP_HUMAN	Affects Expression	[22]
Laminin subunit alpha-3 (LAMA3)	OTFME7HT	LAMA3_HUMAN	Increases Expression	[22]
Atos homolog protein A (ATOSA)	OTWFM5G0	ATOSA_HUMAN	Decreases Expression	[22]
Glycerol-3-phosphate acyltransferase 3 (GPAT3)	OTJUGPK0	GPAT3_HUMAN	Increases Expression	[22]
Quinone oxidoreductase PIG3 (TP53I3)	OTSCM68G	QORX_HUMAN	Increases Expression	[22]
RRP12-like protein (RRP12)	OTQQAEH4	RRP12_HUMAN	Increases Expression	[22]
ALS2 C-terminal-like protein (ALS2CL)	OT8RY7TZ	AL2CL_HUMAN	Affects Expression	[22]
Dynamin-binding protein (DNMBP)	OTMHH14H	DNMBP_HUMAN	Increases Expression	[22]
Ribosomal protein eS27-like (RPS27L)	OTZWHU0N	RS27L_HUMAN	Increases Expression	[22]
Arginine/serine-rich coiled-coil protein 2 (RSRC2)	OTLE0KQM	RSRC2_HUMAN	Decreases Expression	[22]
Mitochondrial enolase superfamily member 1 (ENOSF1)	OT65D3ZK	ENOF1_HUMAN	Decreases Expression	[22]
Ribonucleoside-diphosphate reductase subunit M2 B (RRM2B)	OTE8GBUR	RIR2B_HUMAN	Decreases Expression	[22]
Protein LYRIC (MTDH)	OTGH7N4C	LYRIC_HUMAN	Decreases Expression	[22]
Liprin-beta-1 (PPFIBP1)	OTRA2S7B	LIPB1_HUMAN	Increases Expression	[22]
Dynein axonemal intermediate chain 3 (DNAI3)	OTG1A0QP	DNAI3_HUMAN	Decreases Expression	[22]
Protein O-mannosyl-transferase TMTC2 (TMTC2)	OTY1QWYU	TMTC2_HUMAN	Decreases Expression	[22]
Ninein (NIN)	OTVH3M4Z	NIN_HUMAN	Decreases Expression	[22]
Ceramide synthase 5 (CERS5)	OT5A2DNI	CERS5_HUMAN	Increases Expression	[22]
Uncharacterized protein C8orf58 (C8ORF58)	OTHW01L0	CH058_HUMAN	Increases Expression	[22]
F-box only protein 22 (FBXO22)	OTEJ5MO0	FBX22_HUMAN	Increases Expression	[22]
(Lyso)-N-acylphosphatidylethanolamine lipase (ABHD4)	OTQK3M9X	ABHD4_HUMAN	Increases Expression	[22]
F-box only protein 30 (FBXO30)	OTD1P6LA	FBX30_HUMAN	Decreases Expression	[22]
Pantothenate kinase 1 (PANK1)	OT2CZVRT	PANK1_HUMAN	Decreases Expression	[22]
SH3 domain and tetratricopeptide repeat-containing protein 1 (SH3TC1)	OT0HYZIU	S3TC1_HUMAN	Decreases Expression	[22]
Uncharacterized protein C4orf3 (C4ORF3)	OT6TFN1O	CD003_HUMAN	Decreases Expression	[22]
Paraspeckle component 1 (PSPC1)	OTYS6WQ8	PSPC1_HUMAN	Decreases Expression	[22]
E3 ubiquitin-protein ligase rififylin (RFFL)	OT85MGDH	RFFL_HUMAN	Increases Expression	[22]
Probable ATP-dependent RNA helicase DDX17 (DDX17)	OTXRMMBP	DDX17_HUMAN	Decreases Expression	[22]
GTP-binding protein Rit1 (RIT1)	OTVNOGOH	RIT1_HUMAN	Increases Expression	[22]
KICSTOR complex protein ITFG2 (ITFG2)	OT0NLZ8I	ITFG2_HUMAN	Decreases Expression	[22]
Protein TMEPAI (PMEPA1)	OTY8Z9UF	PMEPA_HUMAN	Increases Expression	[22]
Protein FAM162A (FAM162A)	OT882DND	F162A_HUMAN	Decreases Expression	[22]
Tumor protein p53-inducible nuclear protein 1 (TP53INP1)	OT2363Z9	T53I1_HUMAN	Increases Expression	[22]
SPRY domain-containing SOCS box protein 1 (SPSB1)	OTGY26U4	SPSB1_HUMAN	Increases Expression	[22]
Carboxymethylenebutenolidase homolog (CMBL)	OT8H3S3G	CMBL_HUMAN	Increases Expression	[22]
Protein FAM89A (FAM89A)	OTNASAXT	FA89A_HUMAN	Increases Expression	[22]
ERO1-like protein alpha (ERO1A)	OTVKOQWM	ERO1A_HUMAN	Increases Expression	[22]
Protein FAM210B, mitochondrial (FAM210B)	OT2QHEQ6	F210B_HUMAN	Decreases Expression	[22]
E1A-binding protein p400 (EP400)	OTVQ75NX	EP400_HUMAN	Decreases Expression	[22]
Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)	OT9C3KFI	KKCC2_HUMAN	Increases Expression	[22]
ETS-related transcription factor Elf-4 (ELF4)	OT167PR5	ELF4_HUMAN	Increases Expression	[22]
Eukaryotic translation initiation factor 3 subunit C (EIF3C)	OTR8RF9X	EIF3C_HUMAN	Decreases Expression	[22]
Cancer-related nucleoside-triphosphatase (NTPCR)	OTTRT6Z9	NTPCR_HUMAN	Increases Expression	[22]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[22]
G protein-coupled receptor 88 (GPR88)	OTGAT70V	GPR88_HUMAN	Increases Expression	[22]
Coiled-coil domain-containing protein 90B, mitochondrial (CCDC90B)	OTFFWB0C	CC90B_HUMAN	Decreases Expression	[22]
Polyprenol reductase (SRD5A3)	OT9IJLX7	PORED_HUMAN	Decreases Expression	[22]
E3 ubiquitin ligase RNF121 (RNF121)	OTA0YMLW	RN121_HUMAN	Decreases Expression	[22]
Ankyrin repeat family A protein 2 (ANKRA2)	OTLSLV5A	ANRA2_HUMAN	Decreases Expression	[22]
p53-induced death domain-containing protein 1 (PIDD1)	OTWFM930	PIDD1_HUMAN	Decreases Expression	[22]
ABC-type oligopeptide transporter ABCB9 (ABCB9)	OTSOBOL5	ABCB9_HUMAN	Increases Expression	[22]
Fructose-2,6-bisphosphatase TIGAR (TIGAR)	OTR7NMRJ	TIGAR_HUMAN	Increases Expression	[22]
Dual specificity protein phosphatase 22 (DUSP22)	OTEZ3U85	DUS22_HUMAN	Increases Expression	[22]
PAK4-inhibitor INKA2 (INKA2)	OT9RA64U	INKA2_HUMAN	Increases Expression	[22]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[22]
LIM and cysteine-rich domains protein 1 (LMCD1)	OT3AWE8O	LMCD1_HUMAN	Decreases Expression	[22]
Signal-induced proliferation-associated 1-like protein 2 (SIPA1L2)	OT8NJE5D	SI1L2_HUMAN	Decreases Expression	[22]
Dolichol-phosphate mannosyltransferase subunit 3 (DPM3)	OTSB4XO0	DPM3_HUMAN	Increases Expression	[22]
DnaJ homolog subfamily B member 9 (DNAJB9)	OT38EQT6	DNJB9_HUMAN	Increases Expression	[22]
Mitochondrial fission process protein 1 (MTFP1)	OT3L6F7U	MTFP1_HUMAN	Increases Expression	[22]
SERTA domain-containing protein 1 (SERTAD1)	OTBHKZQP	SRTD1_HUMAN	Increases Expression	[22]
Oxidative stress-induced growth inhibitor 1 (OSGIN1)	OT9KIVZW	OSGI1_HUMAN	Decreases Expression	[22]
Heme transporter FLVCR2 (FLVCR2)	OTAM94ID	FLVC2_HUMAN	Decreases Expression	[22]
Exocyst complex component 7 (EXOC7)	OT4YA137	EXOC7_HUMAN	Increases Expression	[22]
5'-AMP-activated protein kinase subunit beta-1 (PRKAB1)	OT1OG4QZ	AAKB1_HUMAN	Affects Expression	[22]
RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1)	OTHHFW17	CTDP1_HUMAN	Decreases Expression	[22]
Pleckstrin homology-like domain family A member 3 (PHLDA3)	OTXFUDO2	PHLA3_HUMAN	Increases Expression	[22]
Insulin-induced gene 2 protein (INSIG2)	OTX4VY51	INSI2_HUMAN	Increases Expression	[22]
Sestrin-1 (SESN1)	OTSFDZWL	SESN1_HUMAN	Increases Expression	[22]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[33]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Decreases Expression	[34]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[33]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[35]
Glutathione peroxidase 3 (GPX3)	OT6PK94R	GPX3_HUMAN	Decreases Activity	[36]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[35]
Elastin (ELN)	OTFSO7PG	ELN_HUMAN	Increases ADR	[32]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCTT74M	OVCAR3	Investigative	[37]
Clear cell renal cell carcinoma	DC01E1V	786-0	Investigative	[37]
Plasma cell myeloma	DC12ECP	RPMI-8226	Investigative	[37]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [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: 4903).
• [3] Ifosfamide FDA Label
• [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: 7201).
• [5] Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des. 2013;19(5):940-50.
• [6] Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
• [7] Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma. Cell Signal. 2012 Apr;24(4):852-8. doi: 10.1016/j.cellsig.2011.11.020. Epub 2011 Dec 8.
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [9] Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.Drug Des Devel Ther. 2015 Aug 26;9:4897-907.
• [10] Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014 Mar 15;134(6):1484-94.
• [11] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [12] Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7.
• [13] Editor's Highlight: PlacentalDisposition and Effects of Crizotinib: An Ex Vivo Study in the Isolated Dual-Side Perfused Human Cotyledon. Toxicol Sci. 2017 Jun 1;157(2):500-509. doi: 10.1093/toxsci/kfx063.
• [14] Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
• [15] Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer. 2012 Nov 1;118(21):5302-9. doi: 10.1002/cncr.27450. Epub 2012 Apr 4.
• [16] Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63. doi: 10.1021/jm2007613. Epub 2011 Aug 18.
• [17] ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway. Toxicol Appl Pharmacol. 2019 Nov 15;383:114768. doi: 10.1016/j.taap.2019.114768. Epub 2019 Oct 19.
• [18] Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. Epub 2011 Apr 18.
• [19] 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.
• [20] Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011 Dec;78(6):999-1005. doi: 10.1111/j.1747-0285.2011.01239.x. Epub 2011 Oct 31.
• [21] Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
• [22] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [23] Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35.
• [24] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [25] Measurement of 4-hydroxylation of ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyifosfamide. J Cancer Res Clin Oncol. 2002 Jul;128(7):385-92.
• [26] Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res. 1997 May 15;57(10):1946-54.
• [27] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [28] Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos. 1999 Jun;27(6):655-66.
• [29] CYP2C9 polymorphisms in human tumors. Anticancer Res. 2006 Jan-Feb;26(1A):299-305.
• [30] A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem. 2003 Apr 18;278(16):14146-52.
• [31] Advantages of human hepatocyte-derived transformants expressing a series of human cytochrome p450 isoforms for genotoxicity examination. Toxicol Sci. 2010 Aug;116(2):488-97. doi: 10.1093/toxsci/kfq154. Epub 2010 May 27.
• [32] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [33] PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. Cancer Chemother Pharmacol. 2010 Sep;66(4):765-71. doi: 10.1007/s00280-009-1221-4. Epub 2009 Dec 30.
• [34] Abnormalities in serum osteocalcin values in children receiving chemotherapy including ifosfamide. In Vivo. 1992 Mar-Apr;6(2):219-21.
• [35] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [36] Plasma glutathione peroxidase and its relationship to renal proximal tubule function. Mol Genet Metab. 1998 Nov;65(3):238-45. doi: 10.1006/mgme.1998.2760.
• [37] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966