Details of the Drug Combination

General Information of Drug Combination (ID: DC45MNH)

• Drug Combination Name: Pralatrexate + Ixabepilone
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Pralatrexate (DMAO80I): Small molecular drug
  Ixabepilone (DM2OZ3G): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: 786-0
  Zero Interaction Potency (ZIP) Score: 2.83
  Bliss Independence Score: 3.16
  Loewe Additivity Score: 0.97
  LHighest Single Agent (HSA) Score: 1.13

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pralatrexate

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Peripheral T-cell lymphoma	2A90.C	Approved	[2]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[3]

Pralatrexate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Polypeptide deformylase (PDF)	TT9SL3Q	DEFM_HUMAN	Inhibitor	[6]

Pralatrexate Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Folate transporter 1 (SLC19A1)	DTOSN46	S19A1_HUMAN	Substrate	[7]
Proton-coupled folate transporter (SLC46A1)	DTDJEMI	PCFT_HUMAN	Substrate	[7]

Pralatrexate Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Folylpolyglutamate synthase (FPGS)	DECWT2V	FOLC_HUMAN	Metabolism	[8]

Indication(s) of Ixabepilone

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[4]
Breast carcinoma	N.A.	Approved	[5]

Ixabepilone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin (TUB)	TTML2WA	NOUNIPROTAC	Stablizer	[9]

Ixabepilone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Ixabepilone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Astrocytoma	DC7M4UU	U251	Investigative	[1]
Chronic myelogenous leukemia	DCGGPPW	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DC31ALK	TK-10	Investigative	[1]
Breast adenocarcinoma	DCAK4HZ	MDA-MB-468	Investigative	[12]
Carcinoma	DC83LZ8	RXF 393	Investigative	[12]
Colon carcinoma	DC1Z9I7	KM12	Investigative	[12]
Invasive ductal carcinoma	DC1X7FW	HS 578T	Investigative	[12]
Invasive ductal carcinoma	DCNFCJQ	T-47D	Investigative	[12]
Invasive ductal carcinoma	DCH8WVU	BT-549	Investigative	[12]
Adenocarcinoma	DCG52FM	DU-145	Investigative	[13]
Adenocarcinoma	DC76LTM	OVCAR3	Investigative	[13]
Adenocarcinoma	DC94TVP	A549	Investigative	[13]
Adenocarcinoma	DCMMZCL	HT29	Investigative	[13]
Adenocarcinoma	DC3XOXY	HCC-2998	Investigative	[13]
Adenocarcinoma	DC8T9SJ	HCT-15	Investigative	[13]
Adenocarcinoma	DCPX9M9	SW-620	Investigative	[13]
Cutaneous melanoma	DC6CWSM	SK-MEL-5	Investigative	[13]
High grade ovarian serous adenocarcinoma	DCAT01W	OVCAR-5	Investigative	[13]
High grade ovarian serous adenocarcinoma	DCHO683	OVCAR-8	Investigative	[13]
Lung adenocarcinoma	DCY5CN8	HOP-62	Investigative	[13]
Lung adenocarcinoma	DCZWMBC	MDA-MB-231	Investigative	[13]
Lung adenocarcinoma	DC5MIYT	NCI-H522	Investigative	[13]
Malignant melanoma	DC1IODN	UACC62	Investigative	[13]
Melanoma	DCVDIQ1	UACC-257	Investigative	[13]
Melanoma	DCL995A	SK-MEL-2	Investigative	[13]
Minimally invasive lung adenocarcinoma	DCZIF49	NCI-H322M	Investigative	[13]
Prostate carcinoma	DC41ZAT	PC-3	Investigative	[13]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 6840).
• [3] Pralatrexate 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: 6824).
• [5] Ixabepilone FDA Label
• [6] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [7] Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210.
• [8] Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23.
• [9] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [10] Ixabepilone, a novel microtubule-targeting agent for breast cancer, is a substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2011 May;337(2):423-32.
• [11] The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res. 2008 May 1;14(9):2701-9.
• [12] 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.
• [13] 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.