Details of the Drug Combination

General Information of Drug Combination (ID: DCIF7BU)

• Drug Combination Name: Lenvatinib + Raltitrexed
• Indication: Hepatocellular Carcinoma Stage IIIa; Status: Phase 1 [1]
• Component Drugs:
  Lenvatinib (DMB1IU4): Small molecular drug
  Raltitrexed (DMT9K8G): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lenvatinib

Disease Entry	ICD 11	Status	REF
Thyroid cancer	2D10	Approved	[2]
Thyroid gland follicular carcinoma	N.A.	Approved	[3]
Thyroid gland papillary carcinoma	N.A.	Approved	[3]
Hepatocellular carcinoma	2C12.02	Phase 3	[4]
Renal cell carcinoma	2C90	Phase 3	[5]
Melanoma	2C30	Phase 2	[4]
Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[5]
Ovarian cancer	2C73	Phase 1	[6]
Non-small-cell lung cancer	2C25.Y	Application submitted	[5]

Lenvatinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[6]

Lenvatinib Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Indication(s) of Raltitrexed

Disease Entry	ICD 11	Status	REF
Rectal adenocarcinoma	2B92	Approved	[7]

Raltitrexed 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	[10]

Raltitrexed Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]

Raltitrexed Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Annexin A2 (ANXA2)	OTFNS0CC	ANXA2_HUMAN	Increases Expression	[13]
Diamine acetyltransferase 1 (SAT1)	OT52AU22	SAT1_HUMAN	Increases Expression	[13]
10 kDa heat shock protein, mitochondrial (HSPE1)	OT7JSZLB	CH10_HUMAN	Increases Expression	[13]
Thymosin beta-10 (TMSB10)	OTLVZ13T	TYB10_HUMAN	Increases Expression	[13]
FXYD domain-containing ion transport regulator 3 (FXYD3)	OT9PPRHE	FXYD3_HUMAN	Increases Expression	[13]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[14]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Increases Phosphorylation	[14]
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Increases Response To Substance	[15]
Folate receptor alpha (FOLR1)	OT0QZ0H6	FOLR1_HUMAN	Increases Response To Substance	[15]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Response To Substance	[9]
Reduced folate transporter (SLC19A1)	OTWB0BTO	S19A1_HUMAN	Decreases Response To Substance	[16]

References

• [1] ClinicalTrials.gov (NCT05007587) Lenvatinib Plus HAIC of Modified FOLFOX Regime vs Lenvatinib Plus HAIC of ROX Regime in Patients With Advanced HCC
• [2] FDA Approved Drug Products from FDA Official Website. 2018. Application Number: (ANDA) 208627.
• [3] Lenvatinib FDA Label
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Emerging drugs for ovarian cancer. Expert Opin Emerg Drugs. 2008 Sep;13(3):523-36.
• [7] 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: 7403).
• [8] Influence of CYP3A4/5 and ABC transporter polymorphisms on lenvatinib plasma trough concentrations in Japanese patients with thyroid cancer. Sci Rep. 2019 Apr 1;9(1):5404.
• [9] Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer. 2007 Mar 12;96(5):769-75.
• [10] DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96.
• [11] Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 1999 Jun 1;59(11):2532-5.
• [12] Pharmacogenomic importance of ABCG2. Pharmacogenomics. 2008 Aug;9(8):1005-9.
• [13] 5-Fluorouracil: identification of novel downstream mediators of tumour response. Anticancer Res. 2004 Mar-Apr;24(2A):417-23.
• [14] Effect of p53 status and STAT1 on chemotherapy-induced, Fas-mediated apoptosis in colorectal cancer. Cancer Res. 2005 Oct 1;65(19):8951-60. doi: 10.1158/0008-5472.CAN-05-0961.
• [15] Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits -glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64.
• [16] The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Mol Cancer Ther. 2006 Feb;5(2):438-49. doi: 10.1158/1535-7163.MCT-05-0243.