Details of the Drug Combination

General Information of Drug Combination (ID: DCKCLGF)

• Drug Combination Name: Pemetrexed + Bosutinib
• Indication: Carcinoma, Non-Small-Cell Lung; Status: Phase 1 [1]
• Component Drugs:
  Pemetrexed (DMMX2E6): Small molecular drug
  Bosutinib (DMTI8YE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pemetrexed

Disease Entry	ICD 11	Status	REF
Central nervous system lymphoma	2B33.5	Approved	[2]
Epithelioid mesothelioma	2F10	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Malignant pleural mesothelioma	2C26.0	Approved	[3]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Sarcomatoid mesothelioma	N.A.	Approved	[2]
Small-cell lung cancer	2C25.Y	Approved	[2]
Lung neoplasm	N.A.	Investigative	[2]

Pemetrexed Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[8]

Pemetrexed Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Multidrug resistance-associated protein 5 (ABCC5)	DTYVM24	MRP5_HUMAN	Substrate	[11]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[12]
Folate transporter 1 (SLC19A1)	DTOSN46	S19A1_HUMAN	Substrate	[13]
Proton-coupled folate transporter (SLC46A1)	DTDJEMI	PCFT_HUMAN	Substrate	[14]

Pemetrexed Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Increases Activity	[15]
Reduced folate transporter (SLC19A1)	OTWB0BTO	S19A1_HUMAN	Increases Response To Substance	[16]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[17]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[18]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Decreases Expression	[19]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[20]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[21]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Increases Response To Substance	[22]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Increases Response To Substance	[22]
Splicing factor 45 (RBM17)	OT9ROJCL	SPF45_HUMAN	Decreases Response To Substance	[23]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Response To Substance	[6]
Gamma-glutamyl hydrolase (GGH)	OTL71J7T	GGH_HUMAN	Affects Response To Substance	[7]
Nucleophosmin (NPM1)	OTTBYYT0	NPM_HUMAN	Decreases Response To Substance	[24]
ALK tyrosine kinase receptor (ALK)	OTV3P4V8	ALK_HUMAN	Affects Response To Substance	[25]
ATP-binding cassette sub-family C member 11 (ABCC11)	OTVHL7OR	MRP8_HUMAN	Decreases Response To Substance	[26]
GTPase NRas (NRAS)	OTVQ1DG3	RASN_HUMAN	Increases Response To Substance	[22]
Folylpolyglutamate synthase, mitochondrial (FPGS)	OTW3F1ZE	FOLC_HUMAN	Increases Response To Substance	[7]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Response To Substance	[18]

Indication(s) of Bosutinib

Disease Entry	ICD 11	Status	REF
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	N.A.	Approved	[4]
Breast cancer	2C60-2C65	Approved	[5]

Bosutinib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase ABL1 (ABL)	TT3PJMV	ABL1_HUMAN	Inhibitor	[27]
Proto-oncogene c-Src (SRC)	TT6PKBN	SRC_HUMAN	Inhibitor	[27]

Bosutinib Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[28]

Bosutinib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[29]

Bosutinib Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Phosphorylation	[30]
Tyrosine-protein kinase ABL1 (ABL1)	OT09YVXH	ABL1_HUMAN	Decreases Activity	[31]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[32]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[33]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[30]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Phosphorylation	[30]

References

• [1] ClinicalTrials.gov (NCT03023319) Bosutinib in Combination With Pemetrexed in Patients With Selected Metastatic Solid Tumors
• [2] Pemetrexed FDA Label
• [3] 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: 6837).
• [4] Bosutinib 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: 5710).
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• [21] Xanthohumol inhibits non-small cell lung cancer by activating PUMA-mediated apoptosis. Toxicology. 2022 Mar 30;470:153141. doi: 10.1016/j.tox.2022.153141. Epub 2022 Mar 5.
• [22] KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther. 2014 Jun;13(6):1611-24. doi: 10.1158/1535-7163.MCT-13-0649. Epub 2014 Mar 31.
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• [24] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [25] Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011 Apr;6(4):774-80. doi: 10.1097/JTO.0b013e31820cf053.
• [26] ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci. 2010 Nov;101(11):2404-10.
• [27] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [28] In vitro and in vivo identification of ABCB1 as an efflux transporter of bosutinib. J Hematol Oncol. 2015 Jul 7;8:81.
• [29] In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9.
• [30] SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Cancer Res. 2006 Feb 15;66(4):2279-86. doi: 10.1158/0008-5472.CAN-05-2057.
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• [33] 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.