Details of the Drug Combination

General Information of Drug Combination (ID: DCWON88)

• Drug Combination Name: CYCLOPAMINE + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  CYCLOPAMINE (DMEM2SW): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 294.556
  Bliss Independence Score: 300.012
  Loewe Additivity Score: 8.775
  LHighest Single Agent (HSA) Score: 45.519

Molecular Interaction Atlas of This Drug Combination

Indication(s) of CYCLOPAMINE

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

CYCLOPAMINE Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Smoothened homolog (SMO)	TT8J1S3	SMO_HUMAN	Inhibitor	[2]

CYCLOPAMINE Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[9]
Arginase-1 (ARG1)	OTHZITAM	ARGI1_HUMAN	Increases Expression	[9]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[9]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Decreases Expression	[10]
Zinc finger protein GLI1 (GLI1)	OT1BTAJO	GLI1_HUMAN	Affects Expression	[11]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Expression	[10]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[9]
Macrophage mannose receptor 1 (MRC1)	OTTVCOPT	MRC1_HUMAN	Increases Expression	[9]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Decreases Expression	[9]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[9]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Cleavage	[12]
Thyroxine 5-deiodinase (DIO3)	OTNTITOT	IOD3_HUMAN	Decreases Expression	[13]
Protein patched homolog 1 (PTCH1)	OTMG07H5	PTC1_HUMAN	Decreases Expression	[10]
Protein smoothened (SMO)	OTXXE208	SMO_HUMAN	Increases Expression	[10]
Resistin-like beta (RETNLB)	OT9JJQQQ	RETNB_HUMAN	Increases Expression	[9]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Increases Response To Substance	[14]
Insulin-like growth factor-binding protein 6 (IGFBP6)	OTW878VI	IBP6_HUMAN	Increases Response To Substance	[14]

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[3]
High-risk myelofibrosis	2A20.2	Approved	[4]
Myelofibrosis	2A22	Approved	[5]
Myeloproliferative neoplasm	2A20	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Pancreatic cancer	2C10	Phase 3	[4]
Atopic dermatitis	EA80	Phase 1/2	[8]
Vitiligo	ED63.0	Phase 1/2	[8]

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	[15]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[15]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[16]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[17]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[17]

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	[18]

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] Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signali... Bioorg Med Chem Lett. 2009 Jan 15;19(2):328-31.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 5688).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Ruxolitinib FDA Label
• [7] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] M2 macrophage-derived IL6 mediates resistance of breast cancer cells to hedgehog inhibition. Toxicol Appl Pharmacol. 2019 Feb 1;364:77-82. doi: 10.1016/j.taap.2018.12.013. Epub 2018 Dec 19.
• [10] Mono-2-ethyhexyl phthalate advancing the progression of prostate cancer through activating the hedgehog pathway in LNCaP cells. Toxicol In Vitro. 2016 Apr;32:86-91. doi: 10.1016/j.tiv.2015.12.012. Epub 2015 Dec 19.
• [11] Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res. 2009 Nov;29(11):4629-32.
• [12] Effects of combination of notch inhibitor plus hedgehog inhibitor or Wnt inhibitor on growth of leukemia cells. Anticancer Res. 2011 Mar;31(3):893-6.
• [13] MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Endocr Relat Cancer. 2016 Mar;23(3):135-46. doi: 10.1530/ERC-15-0162.
• [14] Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. Int J Oncol. 2012 Nov;41(5):1751-61. doi: 10.3892/ijo.2012.1599. Epub 2012 Aug 22.
• [15] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [16] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [17] 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.
• [18] 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.