Details of the Drug Combination

General Information of Drug Combination (ID: DC5E6GT)

• Drug Combination Name: AZD8055 + Mitotane
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  AZD8055 (DM7L8SG): Small molecular drug
  Mitotane (DMU1GX0): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 3.467
  Bliss Independence Score: 2.763
  Loewe Additivity Score: 0.807
  LHighest Single Agent (HSA) Score: 3.82

Molecular Interaction Atlas of This Drug Combination

Indication(s) of AZD8055

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1/2	[2]

AZD8055 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[4]

Indication(s) of Mitotane

Disease Entry	ICD 11	Status	REF
Adrenocortical carcinoma	2D11.Z	Approved	[3]

Mitotane Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Binder	[5]

Mitotane Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Expression	[6]
Steroidogenic acute regulatory protein, mitochondrial (STAR)	OTFEZ5AI	STAR_HUMAN	Decreases Expression	[7]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[8]
cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A)	OT589JA2	KAP0_HUMAN	Decreases Expression	[8]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[9]
Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1)	OTU0FC24	COX41_HUMAN	Decreases Expression	[9]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Decreases Expression	[10]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[10]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Increases Expression	[11]
Glia-derived nexin (SERPINE2)	OTYF5340	GDN_HUMAN	Increases Expression	[12]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[10]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1)	OTNAZVKB	3BHS1_HUMAN	Decreases Expression	[12]
ETS domain-containing protein Elk-1 (ELK1)	OTH9MXD6	ELK1_HUMAN	Increases Activity	[13]
Ribonucleoside-diphosphate reductase large subunit (RRM1)	OTXGQOR9	RIR1_HUMAN	Increases Expression	[14]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Decreases Expression	[10]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[10]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Increases Activity	[13]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[15]
Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2)	OTCH86VF	AL1L2_HUMAN	Increases Expression	[12]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Decreases Expression	[10]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Increases Expression	[12]

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: 7714).
• [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: 6957).
• [4] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [5] Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs. 2005 Apr;6(4):386-94.
• [6] Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):281-9.
• [7] Mitotane exhibits dual effects on steroidogenic enzymes gene transcription under basal and cAMP-stimulating microenvironments in NCI-H295 cells. Toxicology. 2012 Aug 16;298(1-3):14-23.
• [8] The effect of mitotane on viability, steroidogenesis and gene expression in NCI295R adrenocortical cells. Mol Med Rep. 2013 Mar;7(3):893-900.
• [9] Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells. Endocr Relat Cancer. 2013 May 21;20(3):371-81.
• [10] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [11] Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab. 2006 Jun;91(6):2165-70. doi: 10.1210/jc.2005-2157. Epub 2006 Mar 21.
• [12] Effects of mitotane on gene expression in the adrenocortical cell line NCI-H295R: a microarray study. Pharmacogenomics. 2012 Sep;13(12):1351-61. doi: 10.2217/pgs.12.116.
• [13] Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase. Carcinogenesis. 2009 Jan;30(1):106-13. doi: 10.1093/carcin/bgn213. Epub 2008 Sep 12.
• [14] Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012 Jun 15;18(12):3452-61. doi: 10.1158/1078-0432.CCR-11-2692. Epub 2012 Apr 30.
• [15] Agonistic effects of diverse xenobiotics on the constitutive androstane receptor as detected in a recombinant yeast-cell assay. Toxicol In Vitro. 2018 Feb;46:335-349. doi: 10.1016/j.tiv.2017.09.014. Epub 2017 Sep 18.