Details of the Drug Combination

General Information of Drug Combination (ID: DC1F2RS)

• Drug Combination Name: AT7519 + Mitotane
• Indication: Ewing sarcoma; Status: Investigative [1]
• Component Drugs:
  AT7519 (DMCE08M): Small molecular drug
  Mitotane (DMU1GX0): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TC-71
  Zero Interaction Potency (ZIP) Score: 2.858
  Bliss Independence Score: 2.688
  Loewe Additivity Score: 0.144
  LHighest Single Agent (HSA) Score: 3.372

Molecular Interaction Atlas of This Drug Combination

Indication(s) of AT7519

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

AT7519 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[4]

AT7519 Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[5]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Decreases Expression	[5]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[5]
M-phase inducer phosphatase 1 (CDC25A)	OTSLKKCO	MPIP1_HUMAN	Decreases Expression	[5]
M-phase inducer phosphatase 2 (CDC25B)	OT12MSRY	MPIP2_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[5]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[5]
Forkhead box protein O4 (FOXO4)	OT90X9LN	FOXO4_HUMAN	Increases Expression	[5]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[5]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[5]
Ubiquitin-like-conjugating enzyme ATG10 (ATG10)	OTVRPC5X	ATG10_HUMAN	Decreases Expression	[5]

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	[6]

Mitotane Interacts with 41 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 11B1, mitochondrial (CYP11B1)	OTKKL894	C11B1_HUMAN	Increases Expression	[7]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Expression	[7]
Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A1)	OT2NV3AN	CP11A_HUMAN	Decreases Expression	[8]
Steroid 21-hydroxylase (CYP21A2)	OTN0UDVP	CP21A_HUMAN	Decreases Expression	[8]
Steroidogenic acute regulatory protein, mitochondrial (STAR)	OTFEZ5AI	STAR_HUMAN	Decreases Expression	[8]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[9]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[10]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[11]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Expression	[11]
cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A)	OT589JA2	KAP0_HUMAN	Decreases Expression	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[11]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[11]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[12]
Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1)	OTU0FC24	COX41_HUMAN	Decreases Expression	[12]
Cytochrome P450 11B2, mitochondrial (CYP11B2)	OTIOLWYN	C11B2_HUMAN	Decreases Expression	[12]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Decreases Expression	[13]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[13]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Activity	[14]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Increases Expression	[15]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Affects Binding	[16]
Glia-derived nexin (SERPINE2)	OTYF5340	GDN_HUMAN	Increases Expression	[17]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[13]
Corticosteroid-binding globulin (SERPINA6)	OTOIBEW7	CBG_HUMAN	Increases Expression	[15]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Binding	[16]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1)	OTNAZVKB	3BHS1_HUMAN	Decreases Expression	[17]
Cyclic AMP-responsive element-binding protein 1 (CREB1)	OT1MDLA1	CREB1_HUMAN	Increases Activity	[18]
ETS domain-containing protein Elk-1 (ELK1)	OTH9MXD6	ELK1_HUMAN	Increases Activity	[18]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[13]
Ribonucleoside-diphosphate reductase large subunit (RRM1)	OTXGQOR9	RIR1_HUMAN	Increases Expression	[19]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Decreases Expression	[13]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[13]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Increases Activity	[18]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Decreases Expression	[13]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[20]
Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2)	OTCH86VF	AL1L2_HUMAN	Increases Expression	[17]
Estrogen receptor beta (ESR2)	OTXNR2WQ	ESR2_HUMAN	Increases Activity	[14]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Decreases Expression	[13]
CREB-binding protein (CREBBP)	OTPA4QGM	CBP_HUMAN	Increases Activity	[21]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Increases Expression	[17]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[17]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Response To Substance	[22]

References

• [1] 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.
• [2] ClinicalTrials.gov (NCT02503709) Onalespib and CDKI AT7519 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery in National Cancer Institute (NCI).
• [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] Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32.
• [5] CDK Blockade Using AT7519 Suppresses Acute Myeloid Leukemia Cell Survival through the Inhibition of Autophagy and Intensifies the Anti-leukemic Effect of Arsenic Trioxide. Iran J Pharm Res. 2019 Fall;18(Suppl1):119-131. doi: 10.22037/ijpr.2019.112560.13827.
• [6] Mitotane for adrenocortical carcinoma treatment. Curr Opin Investig Drugs. 2005 Apr;6(4):386-94.
• [7] Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):281-9.
• [8] 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.
• [9] Differential effect of DDT, DDE, and DDD on COX-2 expression in the human trophoblast derived HTR-8/SVneo cells. J Biochem Mol Toxicol. 2012 Nov;26(11):454-60.
• [10] Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor. J Endocrinol. 2013 Feb 15;216(3):297-305.
• [11] The effect of mitotane on viability, steroidogenesis and gene expression in NCI295R adrenocortical cells. Mol Med Rep. 2013 Mar;7(3):893-900.
• [12] 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.
• [13] 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.
• [14] Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor and for improved detection of estrogenic/antiestrogenic chemicals. Environ Toxicol Chem. 2016 Jan;35(1):91-100. doi: 10.1002/etc.3146. Epub 2015 Dec 9.
• [15] 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.
• [16] Recombinant human estrogen, androgen and progesterone receptors for detection of potential endocrine disruptors. Anal Bioanal Chem. 2004 Feb;378(3):664-9. doi: 10.1007/s00216-003-2251-0. Epub 2003 Oct 25.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] The organochlorine o,p'-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells. Environ Health Perspect. 2012 Sep;120(9):1291-6. doi: 10.1289/ehp.1104296. Epub 2012 May 18.
• [22] Interferon- is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane. Endocr Relat Cancer. 2013 May 30;20(3):443-54. doi: 10.1530/ERC-12-0217. Print 2013 Jun.