Details of the Drug Combination

General Information of Drug Combination (ID: DC9DZ77)

• Drug Combination Name: Pyrimethamine + Leucovorin
• Indication: Gangliosidoses, GM2; Status: Phase 1 [1]
• Component Drugs:
  Pyrimethamine (DM5X7VY): Small molecular drug
  Leucovorin (DMUAZWG): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pyrimethamine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]

Pyrimethamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Folate receptor alpha (FOLR1)	TTVC37M	FOLR1_HUMAN	Modulator	[4]

Pyrimethamine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[5]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[6]

Pyrimethamine Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[7]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[8]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[9]
Suppressor of cytokine signaling 3 (SOCS3)	OTY183WJ	SOCS3_HUMAN	Decreases Expression	[10]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[11]
Beta-hexosaminidase subunit beta (HEXB)	OTROYLCR	HEXB_HUMAN	Affects Binding	[12]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Activity	[13]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[14]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[15]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[16]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[13]
Multidrug and toxin extrusion protein 2 (SLC47A2)	OTF2CNRD	S47A2_HUMAN	Decreases Activity	[7]
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Decreases Activity	[17]

Indication(s) of Leucovorin

Disease Entry	ICD 11	Status	REF
Colon adenocarcinoma	N.A.	Approved	[3]
Pervasive developmental disorder	6A00-6A0Z	Approved	[3]
Rectal adenocarcinoma	2B92	Approved	[3]
Rectum mucinous adenocarcinoma	N.A.	Approved	[3]
Colon cancer	2B90.Z	Investigative	[3]
Colon mucinous adenocarcinoma	N.A.	Investigative	[3]
Megaloblastic anemia	N.A.	Investigative	[3]
Methotrexate toxicity	N.A.	Investigative	[3]

Leucovorin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[18]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[19]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[20]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Toxoplasmosis	DC8AF7L	N. A.	Phase 1	[21]

References

• [1] ClinicalTrials.gov (NCT01102686) Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease)
• [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: 4800).
• [3] Leucovorin FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [5] Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34.
• [6] Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity. Drug Metab Dispos. 2018 May;46(5):592-599.
• [7] Interactions between Oroxylin A with the solute carrier transporters and ATP-binding cassette transporters: Drug transporters profile for this flavonoid. Chem Biol Interact. 2020 Jun 1;324:109097. doi: 10.1016/j.cbi.2020.109097. Epub 2020 Apr 16.
• [8] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [9] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [10] The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase. J Biol Chem. 2022 Feb;298(2):101531. doi: 10.1016/j.jbc.2021.101531. Epub 2021 Dec 23.
• [11] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [12] Crystal structure of -hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone. J Med Chem. 2011 Mar 10;54(5):1421-9. doi: 10.1021/jm101443u. Epub 2011 Jan 25.
• [13] Pyrimethamine induces apoptosis of melanoma cells via a caspase and cathepsin double-edged mechanism. Cancer Res. 2008 Jul 1;68(13):5291-300. doi: 10.1158/0008-5472.CAN-08-0222.
• [14] Antifolate activity of pyrimethamine enhances temozolomide-induced cytotoxicity in melanoma cells. Mol Cancer Res. 2009 May;7(5):703-12. doi: 10.1158/1541-7786.MCR-08-0263. Epub 2009 May 12.
• [15] 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.
• [16] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [17] The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs. Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G248-54. doi: 10.1152/ajpgi.00224.2009. Epub 2009 Sep 17.
• [18] Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54.
• [19] Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32.
• [20] Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 2002 Jun 1;62(11):3144-50.
• [21] ClinicalTrials.gov (NCT03258762) Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects