Details of the Drug Combination

General Information of Drug Combination (ID: DCJ3LJ7)

• Drug Combination Name: Midostaurin + Piperaquine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  Midostaurin (DMI6E0R): Small molecular drug
  Piperaquine (DMT70RC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 3.951
  Bliss Independence Score: 3.204
  Loewe Additivity Score: 1.253
  LHighest Single Agent (HSA) Score: 4.779

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Midostaurin

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Approved	[2]
Systemic mastocytosis	2A21.0	Approved	[3]
Chronic myelomonocytic leukaemia	2A40	Phase 2	[4]
Colorectal cancer	2B91.Z	Phase 1	[4]

Midostaurin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Protein kinase C gamma (PRKCG)	TTRFOXJ	KPCG_HUMAN	Inhibitor	[6]
Fms-like tyrosine kinase 3 (FLT-3)	TTGJCWZ	FLT3_HUMAN	Inhibitor	[6]

Midostaurin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Midostaurin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]

Midostaurin Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[9]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Response To Substance	[10]
Glycophorin-A (GYPA)	OTABU4YV	GLPA_HUMAN	Decreases Expression	[11]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Decreases Activity	[12]
Thrombopoietin receptor (MPL)	OTZEN192	TPOR_HUMAN	Increases Expression	[11]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[13]

Indication(s) of Piperaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[5]

Piperaquine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A)	TTZVSJ2	NOUNIPROTAC	Inhibitor	[5]

Piperaquine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Hepatoblastoma	DCSFOHC	HB3	Investigative	[16]

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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2018
• [3] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [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: 5702).
• [5] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [6] 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.
• [7] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [8] Midostaurin, a novel protein kinase inhibitor for the treatment of acute myelogenous leukemia: insights from human absorption, metabolism, and excretion studies of a BDDCS II drug. Drug Metab Dispos. 2017 May;45(5):540-555.
• [9] Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002 Feb;87(2):167-76.
• [10] Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells. PLoS One. 2011;6(9):e25351. doi: 10.1371/journal.pone.0025351. Epub 2011 Sep 28.
• [11] Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells. Toxicol In Vitro. 2009 Sep;23(6):979-85. doi: 10.1016/j.tiv.2009.06.027. Epub 2009 Jun 30.
• [12] FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene. 2005 Dec 15;24(56):8259-67. doi: 10.1038/sj.onc.1208989.
• [13] Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism. Arch Toxicol. 2021 Jan;95(1):67-78. doi: 10.1007/s00204-020-02884-2. Epub 2020 Oct 6.
• [14] Eurartesim - European Medicines Agency
• [15] Open-label crossover study of primaquine and dihydroartemisinin-piperaquine pharmacokinetics in healthy adult thai subjects. Antimicrob Agents Chemother. 2014 Dec;58(12):7340-6.
• [16] 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.