Details of the Drug Combination

General Information of Drug Combination (ID: DCSZ29A)

• Drug Combination Name: Ruxolitinib + Plicamycin
• Indication: Childhood T acute lymphoblastic leukemia; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Plicamycin (DM7C8YV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CCRF-CEM
  Zero Interaction Potency (ZIP) Score: 5.38
  Bliss Independence Score: 15.18
  Loewe Additivity Score: 13.71
  LHighest Single Agent (HSA) Score: 13.45

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[2]
High-risk myelofibrosis	2A20.2	Approved	[3]
Myelofibrosis	2A22	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[3]
Atopic dermatitis	EA80	Phase 1/2	[7]
Vitiligo	ED63.0	Phase 1/2	[7]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[10]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[10]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[11]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[12]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[12]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[13]

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[4]
Testicular cancer	2C80	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[8]
Lung cancer	2C25.0	Investigative	[9]
Ovarian cancer	2C73	Investigative	[9]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[15]

Plicamycin Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[16]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[17]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[18]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[19]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[14]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[18]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[20]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[21]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCAK2AJ	HL-60(TB)	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCVQCXX	MOLT-4	Investigative	[1]
Anaplastic large cell lymphoma	DC7I3LT	SR	Investigative	[1]
Astrocytoma	DCMRJUI	U251	Investigative	[1]
Astrocytoma	DCP0UVE	SNB-19	Investigative	[1]
Chronic myelogenous leukemia	DCT8TVE	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DCMGNCV	TK-10	Investigative	[1]
Clear cell renal cell carcinoma	DCYJKW4	A498	Investigative	[1]
Clear cell renal cell carcinoma	DC0MDOV	786-0	Investigative	[1]
Clear cell renal cell carcinoma	DCN1A5J	CAKI-1	Investigative	[1]
Glioma	DCFUV3H	SF-539	Investigative	[1]
Glioma	DCOXTVC	SF-295	Investigative	[1]
Papillary renal cell carcinoma	DCFL78I	ACHN	Investigative	[1]
Plasma cell myeloma	DC46V0X	RPMI-8226	Investigative	[1]
Carcinoma	DC6XBKU	MCF7	Investigative	[22]
Colon adenocarcinoma	DC4G2QL	COLO 205	Investigative	[22]
Colon carcinoma	DC5BO42	KM12	Investigative	[22]
Invasive ductal carcinoma	DC29QEU	T-47D	Investigative	[22]
Invasive ductal carcinoma	DCR4RZQ	BT-549	Investigative	[22]
Invasive ductal carcinoma	DCDFJDH	HS 578T	Investigative	[22]
Adenocarcinoma	DCROKN8	OVCAR3	Investigative	[23]
Adenocarcinoma	DC47ZNK	SW-620	Investigative	[23]
Adenocarcinoma	DCI2M9Q	HCT-15	Investigative	[23]
Adenocarcinoma	DC0848B	HCT116	Investigative	[23]
Adenocarcinoma	DCL0QDL	HCC-2998	Investigative	[23]
Amelanotic melanoma	DCYYZBV	MDA-MB-435	Investigative	[23]
Cutaneous melanoma	DCD1MDI	SK-MEL-28	Investigative	[23]
Cutaneous melanoma	DC9YSLR	SK-MEL-5	Investigative	[23]
High grade ovarian serous adenocarcinoma	DCULFUI	OVCAR-5	Investigative	[23]
High grade ovarian serous adenocarcinoma	DC0QRAK	OVCAR-8	Investigative	[23]
High grade ovarian serous adenocarcinoma	DCS3AML	OVCAR-4	Investigative	[23]
Large cell lung carcinoma	DCFY4S1	NCI-H460	Investigative	[23]
Melanoma	DCK0CZ0	UACC-257	Investigative	[23]
Melanoma	DCB9JW5	SK-MEL-2	Investigative	[23]
Melanoma	DC2XXRV	MALME-3M	Investigative	[23]
Minimally invasive lung adenocarcinoma	DCZSVC1	NCI-H322M	Investigative	[23]
Non-small cell lung carcinoma	DC700ZP	HOP-92	Investigative	[23]
Prostate carcinoma	DCA079H	PC-3	Investigative	[23]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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: 8394).
• [9] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
• [10] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [11] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [12] The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [14] The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription. Chem Biol Interact. 2014 Aug 5;219:123-32. doi: 10.1016/j.cbi.2014.05.019. Epub 2014 Jun 4.
• [15] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [16] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [17] Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem. 2007 Jan 26;282(4):2615-25. doi: 10.1074/jbc.M606203200. Epub 2006 Nov 22.
• [18] Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6. doi: 10.1016/j.cbi.2009.09.018.
• [19] The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008 Jun;28(3):161-76. doi: 10.1042/BSR20080046.
• [20] Sp sites contribute to basal and inducible expression of the human TNIP1 (TNF-inducible protein 3-interacting protein 1) promoter. Biochem J. 2013 Jun 15;452(3):519-29. doi: 10.1042/BJ20121666.
• [21] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [22] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [23] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976