Details of the Drug Combination

General Information of Drug Combination (ID: DCH070R)

• Drug Combination Name: Rigosertib + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Rigosertib (DMOSTXF): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 4.18
  Bliss Independence Score: 4.18
  Loewe Additivity Score: 6.69
  LHighest Single Agent (HSA) Score: 6.77

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Rigosertib

Disease Entry	ICD 11	Status	REF
Myelodysplastic syndrome	2A37	Phase 3	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[3]

Rigosertib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Polo-like kinase 1 (PLK1)	TTIYVQP	PLK1_HUMAN	Modulator	[8]
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Modulator	[8]

Rigosertib Interacts with 96 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
NF-kappa-B inhibitor epsilon (NFKBIE)	OTLAYEL9	IKBE_HUMAN	Affects Expression	[6]
Nuclear factor 1 B-type (NFIB)	OTX94PD0	NFIB_HUMAN	Increases Expression	[6]
Protein Mdm4 (MDM4)	OTU10BSF	MDM4_HUMAN	Affects Expression	[6]
Protein MTSS 1 (MTSS1)	OT5DTDO2	MTSS1_HUMAN	Increases Expression	[6]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[9]
Cytohesin-interacting protein (CYTIP)	OTRJ3ZC5	CYTIP_HUMAN	Increases Expression	[6]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[10]
2'-5'-oligoadenylate synthase 1 (OAS1)	OT8ZLOCY	OAS1_HUMAN	Decreases Expression	[6]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[11]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[6]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[12]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases Phosphorylation	[7]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[6]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Increases Phosphorylation	[7]
Tyrosine-protein kinase Fyn (FYN)	OTLSLVZS	FYN_HUMAN	Increases Phosphorylation	[7]
Eukaryotic translation initiation factor 4E (EIF4E)	OTDAWNLA	IF4E_HUMAN	Decreases Activity	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[6]
Transcriptional activator Myb (MYB)	OTJH64IV	MYB_HUMAN	Affects Localization	[13]
cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A)	OT589JA2	KAP0_HUMAN	Increases Expression	[6]
Fatty acid-binding protein, adipocyte (FABP4)	OT3DKFOU	FABP4_HUMAN	Affects Expression	[6]
Ezrin (EZR)	OTHBPF1Z	EZRI_HUMAN	Increases Expression	[6]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Increases Expression	[6]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[14]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[6]
Transcription factor E3 (TFE3)	OTM99ZWH	TFE3_HUMAN	Affects Expression	[6]
Lamin-B1 (LMNB1)	OT100T3P	LMNB1_HUMAN	Increases Cleavage	[10]
B-cell differentiation antigen CD72 (CD72)	OTPOJID2	CD72_HUMAN	Decreases Expression	[6]
Tyrosine-protein phosphatase non-receptor type 6 (PTPN6)	OT33XNZM	PTN6_HUMAN	Decreases Expression	[6]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[11]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[15]
Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (MAN1A1)	OT6LIGJP	MA1A1_HUMAN	Increases Expression	[6]
Tyrosine-protein kinase RYK (RYK)	OTZ3WWZH	RYK_HUMAN	Decreases Phosphorylation	[7]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Phosphorylation	[7]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[6]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[6]
Interleukin-6 receptor subunit beta (IL6ST)	OT1N9C70	IL6RB_HUMAN	Increases Expression	[6]
ETS translocation variant 5 (ETV5)	OTE2OBM4	ETV5_HUMAN	Increases Expression	[6]
Regulator of G-protein signaling 2 (RGS2)	OT0FSRW7	RGS2_HUMAN	Increases Expression	[6]
Tyrosine-protein kinase FRK (FRK)	OTEKV1SC	FRK_HUMAN	Increases Phosphorylation	[7]
Nuclear receptor subfamily 4 group A member 2 (NR4A2)	OT3F9IR2	NR4A2_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Phosphorylation	[7]
Ran GTPase-activating protein 1 (RANGAP1)	OTZGD3LJ	RAGP1_HUMAN	Increases Phosphorylation	[16]
Crk-like protein (CRKL)	OTOYSD1R	CRKL_HUMAN	Decreases Phosphorylation	[17]
Max-interacting protein 1 (MXI1)	OTUQ9E0D	MXI1_HUMAN	Increases Expression	[6]
Tyrosine-protein kinase Blk (BLK)	OT1EB8MT	BLK_HUMAN	Increases Phosphorylation	[7]
Protein FosB (FOSB)	OTW6C05J	FOSB_HUMAN	Decreases Expression	[6]
Epithelial membrane protein 1 (EMP1)	OTSZHUHQ	EMP1_HUMAN	Increases Expression	[6]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Decreases Expression	[11]
Claudin-15 (CLDN15)	OT9K0KI7	CLD15_HUMAN	Affects Expression	[6]
Actin, cytoplasmic 1 (ACTB)	OT1MCP2F	ACTB_HUMAN	Increases Expression	[6]
Rho-related GTP-binding protein RhoB (RHOB)	OTHQFQF7	RHOB_HUMAN	Increases Expression	[6]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[18]
Actin, cytoplasmic 2 (ACTG1)	OTH4V7VQ	ACTG_HUMAN	Increases Expression	[6]
Tropomyosin alpha-4 chain (TPM4)	OTN4YLYR	TPM4_HUMAN	Increases Expression	[6]
Histone H3.3 (H3-3B)	OT9XHQ3C	H33_HUMAN	Increases Expression	[6]
cAMP-responsive element modulator (CREM)	OTJIJ5AL	CREM_HUMAN	Increases Expression	[6]
Histone-lysine N-methyltransferase 2A (KMT2A)	OT9GLJI6	KMT2A_HUMAN	Increases Expression	[6]
Dual specificity protein phosphatase 2 (DUSP2)	OTH54FMR	DUS2_HUMAN	Decreases Expression	[6]
3',5'-cyclic-AMP phosphodiesterase 4B (PDE4B)	OTOA8WU2	PDE4B_HUMAN	Increases Expression	[6]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[11]
Son of sevenless homolog 2 (SOS2)	OTV3XRE5	SOS2_HUMAN	Increases Expression	[6]
Inositol 1,4,5-triphosphate receptor associated 2 (IRAG2)	OTLUTKJQ	IRAG2_HUMAN	Affects Expression	[6]
Dual specificity protein phosphatase 4 (DUSP4)	OT6WAO12	DUS4_HUMAN	Increases Expression	[6]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[6]
Krueppel-like factor 5 (KLF5)	OT1ABI9N	KLF5_HUMAN	Increases Expression	[6]
Protein-tyrosine kinase 2-beta (PTK2B)	OTGAS0I8	FAK2_HUMAN	Increases Phosphorylation	[7]
Genetic suppressor element 1 (GSE1)	OT3J7CJB	GSE1_HUMAN	Affects Expression	[6]
Nuclear mitotic apparatus protein 1 (NUMA1)	OTTKAVG4	NUMA1_HUMAN	Affects Localization	[19]
Astrocytic phosphoprotein PEA-15 (PEA15)	OTKCKTSX	PEA15_HUMAN	Increases Expression	[6]
Interferon regulatory factor 4 (IRF4)	OT1DHQ1P	IRF4_HUMAN	Affects Expression	[6]
Microtubule-associated protein RP/EB family member 1 (MAPRE1)	OTCVQD60	MARE1_HUMAN	Affects Localization	[19]
Exostosin-1 (EXT1)	OTRPALJK	EXT1_HUMAN	Increases Expression	[6]
Serine/arginine-rich splicing factor 7 (SRSF7)	OTRS4W4S	SRSF7_HUMAN	Increases Expression	[6]
Pleckstrin homology-like domain family A member 2 (PHLDA2)	OTMV9DPP	PHLA2_HUMAN	Increases Expression	[6]
Histone H2A.V (H2AZ2)	OT0I5H2P	H2AV_HUMAN	Increases Expression	[6]
Syntaxin-12 (STX12)	OT5IBQ62	STX12_HUMAN	Increases Expression	[6]
Polycomb group protein ASXL1 (ASXL1)	OTX931AW	ASXL1_HUMAN	Increases Expression	[6]
DDB1- and CUL4-associated factor 11 (DCAF11)	OTNSGYK1	DCA11_HUMAN	Increases Expression	[6]
Protein NDRG1 (NDRG1)	OTVO66BO	NDRG1_HUMAN	Increases Expression	[6]
TRAF family member-associated NF-kappa-B activator (TANK)	OTZSGFIK	TANK_HUMAN	Increases Expression	[6]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Phosphorylation	[14]
MAP/microtubule affinity-regulating kinase 4 (MARK4)	OT6Z2TGV	MARK4_HUMAN	Increases Expression	[6]
Tribbles homolog 1 (TRIB1)	OTPEO17G	TRIB1_HUMAN	Increases Expression	[6]
Krueppel-like factor 6 (KLF6)	OTQY9S7F	KLF6_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase kinase kinase 3 (MAP3K3)	OT53LJGW	M3K3_HUMAN	Affects Expression	[6]
Calsyntenin-3 (CLSTN3)	OTPUFK4C	CSTN3_HUMAN	Affects Expression	[6]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[6]
Bcl-2-associated transcription factor 1 (BCLAF1)	OT7T8H6A	BCLF1_HUMAN	Increases Expression	[6]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[6]
ADP-ribosylation factor-binding protein GGA2 (GGA2)	OT43HO27	GGA2_HUMAN	Increases Expression	[6]
F-box only protein 2 (FBXO2)	OTF3677S	FBX2_HUMAN	Affects Expression	[6]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Increases Expression	[6]
Disheveled-associated activator of morphogenesis 1 (DAAM1)	OT0VHIYZ	DAAM1_HUMAN	Increases Expression	[6]
Krueppel-like factor 12 (KLF12)	OTVH4KD4	KLF12_HUMAN	Increases Expression	[6]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Affects Response To Substance	[18]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[4]
Acute myeloid leukaemia	2A60	Approved	[5]
Adult acute monocytic leukemia	N.A.	Approved	[4]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[21]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[22]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[23]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[24]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[24]

Idarubicin Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[25]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[20]

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: 7833).
• [4] Idarubicin FDA Label
• [5] 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: 7083).
• [6] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [7] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [8] Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin Cancer Res. 2014 Mar 15;20(6):1656-65.
• [9] Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity. J Med Chem. 2011 Sep 22;54(18):6254-76. doi: 10.1021/jm200570p. Epub 2011 Aug 17.
• [10] Effect of ON 01910.Na, an anticancer mitotic inhibitor, on cell-cycle progression correlates with RanGAP1 hyperphosphorylation. Cancer Res. 2011 Jul 15;71(14):4968-76. doi: 10.1158/0008-5472.CAN-10-1603. Epub 2011 Jun 6.
• [11] Styryl sulfonyl compounds inhibit translation of cyclin D1 in mantle cell lymphoma cells. Oncogene. 2009 Mar 26;28(12):1518-28. doi: 10.1038/onc.2008.502. Epub 2009 Feb 9.
• [12] Discontinuous drug binding to proteins: binding of an antineoplastic benzyl styryl sulfone to albumin and enzymes in vitro and in phase I clinical trials. Drug Metab Dispos. 2010 Sep;38(9):1480-5. doi: 10.1124/dmd.110.033001. Epub 2010 May 25.
• [13] ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex. Transl Res. 2016 Sep;175:129-143.e13. doi: 10.1016/j.trsl.2016.04.001. Epub 2016 Apr 13.
• [14] In vitro antitumor mechanism of (E)-N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide. Mol Pharmacol. 2015 Jan;87(1):18-30. doi: 10.1124/mol.114.093245. Epub 2014 Oct 14.
• [15] A fine-needle aspirate-based vulnerability assay identifies polo-like kinase 1 as a mediator of gemcitabine resistance in pancreatic cancer. Mol Cancer Ther. 2010 Feb;9(2):311-8. doi: 10.1158/1535-7163.MCT-09-0693. Epub 2010 Jan 26.
• [16] Ran GTPase-activating protein 1 is a therapeutic target in diffuse large B-cell lymphoma. PLoS One. 2013 Nov 6;8(11):e79863. doi: 10.1371/journal.pone.0079863. eCollection 2013.
• [17] Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells. Oncotarget. 2015 Aug 21;6(24):20231-40. doi: 10.18632/oncotarget.4047.
• [18] The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas. Mol Cancer Ther. 2013 Oct;12(10):1994-2005. doi: 10.1158/1535-7163.MCT-13-0206. Epub 2013 Jul 19.
• [19] Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. Mol Cancer Ther. 2014 May;13(5):1054-66. doi: 10.1158/1535-7163.MCT-13-0685. Epub 2014 Apr 18.
• [20] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [21] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [22] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [23] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [24] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [25] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.