Details of the Drug Combination

General Information of Drug Combination (ID: DC7MDE5)

• Drug Combination Name: KN-62 + Naltrexone
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  KN-62 (DMLZ89P): Small molecular drug
  Naltrexone (DMUL45H): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 2.686
  Bliss Independence Score: 2.906
  Loewe Additivity Score: 1.306
  LHighest Single Agent (HSA) Score: 4.994

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	[8]
Protein kinase C alpha (PRKCA)	TTFJ8Q1	KPCA_HUMAN	Inhibitor	[8]
Stress-activated protein kinase JNK1 (JNK1)	TT0K6EO	MK08_HUMAN	Inhibitor	[8]
Rho-associated protein kinase 1 (ROCK1)	TTZN7RP	ROCK1_HUMAN	Inhibitor	[8]
Stress-activated protein kinase 2b (p38 beta)	TT73U6C	MK11_HUMAN	Inhibitor	[8]
Extracellular signal-regulated kinase 2 (ERK2)	TT4TQBX	MK01_HUMAN	Inhibitor	[8]
Checkpoint kinase-1 (CHK1)	TTTU902	CHK1_HUMAN	Inhibitor	[8]
P2X purinoceptor 7 (P2RX7)	TT473XN	P2RX7_HUMAN	Inhibitor	[9]
Serine/threonine-protein kinase Sgk1 (SGK1)	TTTV8EJ	SGK1_HUMAN	Inhibitor	[8]
Stress-activated protein kinase 2a (p38 alpha)	TTQBR95	MK14_HUMAN	Inhibitor	[8]
RAC-alpha serine/threonine-protein kinase (AKT1)	TTWTSCV	AKT1_HUMAN	Inhibitor	[8]
MAP kinase p38 (MAPK12)	TTYT93M	MK12_HUMAN	Inhibitor	[8]
Ribosomal protein S6 kinase beta-1 (S6K1)	TTG0U4H	KS6B1_HUMAN	Inhibitor	[8]

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	[8]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Activity	[8]
MAP kinase-activated protein kinase 5 (MAPKAPK5)	OTAZHPVK	MAPK5_HUMAN	Decreases Activity	[8]
Integrin alpha-M (ITGAM)	OTAG6HWU	ITAM_HUMAN	Increases Expression	[10]

Indication(s) of Naltrexone

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[3]
Chronic alcoholism	6C40.2Z	Approved	[4]
Crohn disease	DD70	Approved	[5]
Gastroparesis	DA41.00	Approved	[5]
Inflammatory bowel disease	DD72	Approved	[5]
Obesity	5B81	Approved	[5]
Ulcerative colitis	DD71	Approved	[5]
Human immunodeficiency virus infection	1C62	Phase 4	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Chronic pain	MG30	Investigative	[5]

Naltrexone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Antagonist	[11]

Naltrexone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[12]

Naltrexone Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Activity	[13]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[14]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[14]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Affects Response To Substance	[11]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[11]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[15]
Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)	OTAOZIGX	GBRB2_HUMAN	Affects Response To Substance	[16]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[16]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Response To Substance	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
DD2	DCM1R1U	DD2	Investigative	[17]

References

• [1] 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.
• [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] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 074918.
• [5] Naltrexone FDA Label
• [6] 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: 1639).
• [7] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [8] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [9] Synthesis and structure-activity relationships of pyrazolodiazepine derivatives as human P2X7 receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6053-8.
• [10] 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.
• [11] An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry. 2008 Feb;65(2):135-44.
• [12] In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat. Biochem Pharmacol. 2008 Sep 1;76(5):672-9.
• [13] Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-4.
• [14] Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients. J Clin Endocrinol Metab. 1995 May;80(5):1739-42. doi: 10.1210/jcem.80.5.7745028.
• [15] Association between the Stin2 VNTR polymorphism of the serotonin transporter gene and treatment outcome in alcohol-dependent patients. Alcohol Alcohol. 2008 Sep-Oct;43(5):516-22. doi: 10.1093/alcalc/agn048. Epub 2008 Jun 14.
• [16] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.
• [17] 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.