Details of the Drug Combination

General Information of Drug Combination (ID: DCD4SM1)

• Drug Combination Name: KN-62 + Tranylcypromine
• Indication: DD2; Status: Investigative [1]
• Component Drugs:
  KN-62 (DMLZ89P): Small molecular drug
  Tranylcypromine (DMGB5RE): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DD2
  Zero Interaction Potency (ZIP) Score: 0.802
  Bliss Independence Score: 2.91
  Loewe Additivity Score: 3.249
  LHighest Single Agent (HSA) Score: 2.25

Molecular Interaction Atlas of This Drug Combination

Indication(s) of KN-62

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

KN-62 Interacts with 13 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
LCK tyrosine protein kinase (LCK)	TT860QF	LCK_HUMAN	Inhibitor	[5]
Protein kinase C alpha (PRKCA)	TTFJ8Q1	KPCA_HUMAN	Inhibitor	[5]
Stress-activated protein kinase JNK1 (JNK1)	TT0K6EO	MK08_HUMAN	Inhibitor	[5]
Rho-associated protein kinase 1 (ROCK1)	TTZN7RP	ROCK1_HUMAN	Inhibitor	[5]
Stress-activated protein kinase 2b (p38 beta)	TT73U6C	MK11_HUMAN	Inhibitor	[5]
Extracellular signal-regulated kinase 2 (ERK2)	TT4TQBX	MK01_HUMAN	Inhibitor	[5]
Checkpoint kinase-1 (CHK1)	TTTU902	CHK1_HUMAN	Inhibitor	[5]
P2X purinoceptor 7 (P2RX7)	TT473XN	P2RX7_HUMAN	Inhibitor	[6]
Serine/threonine-protein kinase Sgk1 (SGK1)	TTTV8EJ	SGK1_HUMAN	Inhibitor	[5]
Stress-activated protein kinase 2a (p38 alpha)	TTQBR95	MK14_HUMAN	Inhibitor	[5]
RAC-alpha serine/threonine-protein kinase (AKT1)	TTWTSCV	AKT1_HUMAN	Inhibitor	[5]
MAP kinase p38 (MAPK12)	TTYT93M	MK12_HUMAN	Inhibitor	[5]
Ribosomal protein S6 kinase beta-1 (S6K1)	TTG0U4H	KS6B1_HUMAN	Inhibitor	[5]

KN-62 Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
MAP kinase-activated protein kinase 2 (MAPKAPK2)	OT460SBO	MAPK2_HUMAN	Decreases Activity	[5]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Activity	[5]
MAP kinase-activated protein kinase 5 (MAPKAPK5)	OTAZHPVK	MAPK5_HUMAN	Decreases Activity	[5]
Integrin alpha-M (ITGAM)	OTAG6HWU	ITAM_HUMAN	Increases Expression	[7]

Indication(s) of Tranylcypromine

Disease Entry	ICD 11	Status	REF
Major depressive disorder	6A70.3	Approved	[3]
Prostate cancer	2C82.0	Patented	[4]

Tranylcypromine Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	Inhibitor	[4]
Monoamine oxidase type B (MAO-B)	TTGP7BY	AOFB_HUMAN	Inhibitor	[8]
Monoamine oxidase type A (MAO-A)	TT3WG5C	AOFA_HUMAN	Inhibitor	[9]

Tranylcypromine Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[10]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[11]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[12]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[13]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[14]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Decreases Activity	[15]

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: 6001).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Novel monoamine oxidase inhibitors: a patent review (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):91-110.
• [5] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [6] Synthesis and structure-activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6053-8.
• [7] CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells. J Clin Invest. 2007 May;117(5):1412-21. doi: 10.1172/JCI30779. Epub 2007 Apr 12.
• [8] Tranylcypromine: new perspectives on an "old" drug. Eur Arch Psychiatry Clin Neurosci. 2006 Aug;256(5):268-73.
• [9] Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice. Int J Neuropsychopharmacol. 2009 Mar 11:1-11.
• [10] In vitro inhibition of human small intestinal and liver microsomal astemizole O-demethylation: different contribution of CYP2J2 in the small intestine and liver. Xenobiotica. 2003 Jun;33(6):615-23.
• [11] Validated assays for human cytochrome P450 activities. Drug Metab Dispos. 2004 Jun;32(6):647-60.
• [12] Drug-drug interactions of Z-338, a novel gastroprokinetic agent, with terfenadine, comparison with cisapride, and involvement of UGT1A9 and 1A8 in the human metabolism of Z-338. Eur J Pharmacol. 2004 Aug 23;497(2):223-31.
• [13] Predictive three-dimensional quantitative structure-activity relationship of cytochrome P450 1A2 inhibitors. J Med Chem. 2005 Jun 2;48(11):3808-15.
• [14] Interactions of sesquiterpenes zederone and germacrone with the human cytochrome P450 system. Toxicol In Vitro. 2013 Sep;27(6):2005-12.
• [15] Mimicking gene defects to treat drug dependence. Ann N Y Acad Sci. 2000;909:233-46. doi: 10.1111/j.1749-6632.2000.tb06685.x.