Details of the Drug Combination

General Information of Drug Combination (ID: DC0UJFJ)

• Drug Combination Name: PHA-739358 + Zileuton
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  PHA-739358 (DMGYBZI): Small molecular drug
  Zileuton (DMVRIC2): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 29.2
  Bliss Independence Score: 29.2
  Loewe Additivity Score: 42.53
  LHighest Single Agent (HSA) Score: 42.53

Molecular Interaction Atlas of This Drug Combination

Indication(s) of PHA-739358

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Phase 2	[2]

PHA-739358 Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aurora kinase B (AURKB)	TT5LS6T	AURKB_HUMAN	Inhibitor	[5]
Aurora B messenger RNA (AURKB mRNA)	TT9RTBL	AURKB_HUMAN	Inhibitor	[6]
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[5]
Aurora kinase C (AURKC)	TTLYXIT	AURKC_HUMAN	Inhibitor	[6]

PHA-739358 Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Response To Substance	[7]

Indication(s) of Zileuton

Disease Entry	ICD 11	Status	REF
Allergic asthma	CA23.0	Approved	[3]
Asthma	CA23	Approved	[4]
Intrinsic asthma	N.A.	Approved	[3]

Zileuton Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Arachidonate 5-lipoxygenase (5-LOX)	TT2J34L	LOX5_HUMAN	Inhibitor	[8]

Zileuton Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[9]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[9]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [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: 7937).
• [3] Zileuton FDA Label
• [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: 5297).
• [5] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [6] Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. J Med Chem. 2005 Apr 21;48(8):3080-4.
• [7] Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. PLoS One. 2011 Apr 26;6(4):e19164. doi: 10.1371/journal.pone.0019164.
• [8] 5-lipoxygenase inhibitor zileuton attenuates ischemic brain damage: involvement of matrix metalloproteinase 9. Neurol Res. 2009 Oct;31(8):848-52.
• [9] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [10] Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218.
• [11] Identification of the human liver cytochrome P450 enzymes involved in the metabolism of zileuton (ABT-077) and its N-dehydroxylated metabolite, Abbott-66193. Drug Metab Dispos. 1995 Oct;23(10):1163-74.