Details of the Drug Combination

General Information of Drug Combination (ID: DCLOVO9)

• Drug Combination Name: MK-2206 + PD-0325901
• Indication: Invasive ductal carcinoma; Status: Investigative [1]
• Component Drugs:
  MK-2206 (DMT1OZ6): Small molecular drug
  PD-0325901 (DM27D4J): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T-47D
  Zero Interaction Potency (ZIP) Score: 6.28
  Bliss Independence Score: 5.04
  Loewe Additivity Score: 4.18
  LHighest Single Agent (HSA) Score: 6.33

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-2206

Disease Entry	ICD 11	Status	REF
Rectal adenocarcinoma	2B92	Phase 2	[2]
Nasopharyngeal carcinoma	2B6B	Investigative	[3]

MK-2206 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RAC-gamma serine/threonine-protein kinase (AKT3)	TTAZ05C	AKT3_HUMAN	Modulator	[6]
E2 ubiquitin-conjugating enzyme T (UBE2T)	TT0A1R8	UBE2T_HUMAN	Inhibitor	[3]

MK-2206 Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Expression	[7]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[5]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases Expression	[7]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[5]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[5]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[8]
Vascular endothelial growth factor receptor 1 (FLT1)	OTT0OGYS	VGFR1_HUMAN	Decreases Expression	[5]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[5]
Endothelin receptor type B (EDNRB)	OTLLZV3P	EDNRB_HUMAN	Increases Expression	[5]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Affects Response To Substance	[9]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[10]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[5]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[10]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[5]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[11]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[10]
Interferon regulatory factor 8 (IRF8)	OT8YSNI4	IRF8_HUMAN	Decreases Expression	[5]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[10]
Proline-rich AKT1 substrate 1 (AKT1S1)	OT4JHN4Y	AKTS1_HUMAN	Decreases Phosphorylation	[12]

Indication(s) of PD-0325901

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 2	[4]

PD-0325901 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[14]

PD-0325901 Interacts with 84 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[15]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[15]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Increases Expression	[15]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Decreases Expression	[15]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Decreases Expression	[13]
Neuropilin-1 (NRP1)	OTCGULYV	NRP1_HUMAN	Decreases Expression	[13]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Decreases Expression	[13]
Protein sprouty homolog 2 (SPRY2)	OTH0CRCZ	SPY2_HUMAN	Decreases Expression	[13]
Leupaxin (LPXN)	OTUNV3CK	LPXN_HUMAN	Decreases Expression	[13]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[13]
Slit homolog 2 protein (SLIT2)	OTLS2RJ4	SLIT2_HUMAN	Decreases Expression	[13]
Tumor necrosis factor ligand superfamily member 15 (TNFSF15)	OTNGA2BW	TNF15_HUMAN	Decreases Expression	[13]
Integrin beta-like protein 1 (ITGBL1)	OTJDHE17	ITGBL_HUMAN	Decreases Expression	[13]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Expression	[13]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[13]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[13]
Glycophorin-C (GYPC)	OTOEDR7O	GLPC_HUMAN	Decreases Expression	[13]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Decreases Expression	[13]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[13]
Tissue factor pathway inhibitor (TFPI)	OTA0FX16	TFPI1_HUMAN	Decreases Expression	[13]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Expression	[13]
Aminopeptidase N (ANPEP)	OTP3WYFD	AMPN_HUMAN	Decreases Expression	[13]
Integrin alpha-2 (ITGA2)	OTPFL017	ITA2_HUMAN	Decreases Expression	[13]
Protein-glutamine gamma-glutamyltransferase 2 (TGM2)	OT6MFOWF	TGM2_HUMAN	Decreases Expression	[13]
Pentraxin-related protein PTX3 (PTX3)	OTPXHRKU	PTX3_HUMAN	Decreases Expression	[13]
5-hydroxytryptamine receptor 7 (HTR7)	OT44DEWB	5HT7R_HUMAN	Decreases Expression	[13]
Glutaredoxin-1 (GLRX)	OT0QHTAR	GLRX1_HUMAN	Decreases Expression	[13]
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[13]
ETS translocation variant 5 (ETV5)	OTE2OBM4	ETV5_HUMAN	Decreases Expression	[13]
ETS translocation variant 4 (ETV4)	OT8C98UZ	ETV4_HUMAN	Decreases Expression	[13]
Transcription factor SOX-9 (SOX9)	OTVDJFGN	SOX9_HUMAN	Decreases Expression	[13]
ETS translocation variant 1 (ETV1)	OT6PMJIK	ETV1_HUMAN	Decreases Expression	[13]
Stanniocalcin-1 (STC1)	OTGVVXYF	STC1_HUMAN	Decreases Expression	[13]
Paired mesoderm homeobox protein 1 (PRRX1)	OTTZK5G8	PRRX1_HUMAN	Decreases Expression	[13]
Epithelial membrane protein 1 (EMP1)	OTSZHUHQ	EMP1_HUMAN	Decreases Expression	[13]
Forkhead box protein G1 (FOXG1)	OTAW57J4	FOXG1_HUMAN	Decreases Expression	[13]
ADP-ribosylation factor-like protein 4C (ARL4C)	OTQ3QNNU	ARL4C_HUMAN	Decreases Expression	[13]
Reelin (RELN)	OTLKMW1O	RELN_HUMAN	Decreases Expression	[13]
C-C motif chemokine 20 (CCL20)	OTUCJY4N	CCL20_HUMAN	Decreases Expression	[13]
A-kinase anchor protein 12 (AKAP12)	OTCVRDDX	AKA12_HUMAN	Decreases Expression	[13]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Decreases Expression	[13]
Dual specificity protein phosphatase 4 (DUSP4)	OT6WAO12	DUS4_HUMAN	Decreases Expression	[13]
Semaphorin-3A (SEMA3A)	OTQJSV7W	SEM3A_HUMAN	Decreases Expression	[13]
Monocyte to macrophage differentiation factor (MMD)	OTB5I4OC	PAQRB_HUMAN	Decreases Expression	[13]
Syntaxin-1A (STX1A)	OTSBUZB4	STX1A_HUMAN	Decreases Expression	[13]
Dual specificity protein phosphatase 6 (DUSP6)	OT4H6RKW	DUS6_HUMAN	Decreases Expression	[13]
Kinesin-like protein KIF24 (KIF24)	OTJTA5V3	KIF24_HUMAN	Decreases Expression	[13]
Anoctamin-1 (ANO1)	OTSREUNI	ANO1_HUMAN	Decreases Expression	[13]
NADH-cytochrome b5 reductase 2 (CYB5R2)	OTTLM7XN	NB5R2_HUMAN	Decreases Expression	[13]
Dynamin-binding protein (DNMBP)	OTMHH14H	DNMBP_HUMAN	Decreases Expression	[13]
Sialic acid-binding Ig-like lectin 15 (SIGLEC15)	OTON4K9S	SIG15_HUMAN	Decreases Expression	[13]
UPF0606 protein KIAA1549L (KIAA1549L)	OT80HUVY	K154L_HUMAN	Decreases Expression	[13]
Neuron navigator 3 (NAV3)	OT97M1TR	NAV3_HUMAN	Decreases Expression	[13]
Dedicator of cytokinesis protein 4 (DOCK4)	OTH3XY8B	DOCK4_HUMAN	Decreases Expression	[13]
Transmembrane protein 156 (TMEM156)	OTH7YJID	TM156_HUMAN	Decreases Expression	[13]
Tribbles homolog 2 (TRIB2)	OTHSX3MX	TRIB2_HUMAN	Decreases Expression	[13]
Hyaluronan synthase 2 (HAS2)	OTTD3PAL	HYAS2_HUMAN	Decreases Expression	[13]
Neuronal cell adhesion molecule (NRCAM)	OT80HHQ2	NRCAM_HUMAN	Decreases Expression	[13]
Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2)	OTB71I02	DCBD2_HUMAN	Decreases Expression	[13]
Formin-like protein 2 (FMNL2)	OT9OVWCV	FMNL2_HUMAN	Decreases Expression	[13]
Monoglyceride lipase (MGLL)	OT5ES4IE	MGLL_HUMAN	Decreases Expression	[13]
Paternally-expressed gene 3 protein (PEG3)	OTHQW98S	PEG3_HUMAN	Decreases Expression	[13]
Disintegrin and metalloproteinase domain-containing protein 19 (ADAM19)	OTH88TXU	ADA19_HUMAN	Decreases Expression	[13]
Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15)	OTGMPVNR	S6A15_HUMAN	Decreases Expression	[13]
Endothelial cell-specific molecule 1 (ESM1)	OT331Y8V	ESM1_HUMAN	Decreases Expression	[13]
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1)	OTW3T4B2	IRPL1_HUMAN	Decreases Expression	[13]
Neurotrimin (NTM)	OTHF0UQU	NTRI_HUMAN	Decreases Expression	[13]
Histone deacetylase 9 (HDAC9)	OTO8O0LF	HDAC9_HUMAN	Decreases Expression	[13]
Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6)	OTB17Q43	SIA10_HUMAN	Decreases Expression	[13]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[16]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[17]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[18]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Decreases Expression	[19]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[20]
Fos-related antigen 1 (FOSL1)	OT9YTYMB	FOSL1_HUMAN	Decreases Expression	[21]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[22]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[22]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[20]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[23]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Decreases Activity	[24]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[16]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[20]
DNA repair endonuclease XPF (ERCC4)	OTFIOPG1	XPF_HUMAN	Increases Expression	[19]
Ras-related C3 botulinum toxin substrate 1 (RAC1)	OTKRO61U	RAC1_HUMAN	Affects Response To Substance	[25]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCZVZ9P	CAOV3	Investigative	[26]
Adenocarcinoma	DCB22JO	OVCAR3	Investigative	[26]
Adenocarcinoma	DCWFQB4	A427	Investigative	[26]
Adenocarcinoma	DCAKRPF	NCIH1650	Investigative	[26]
Adenocarcinoma	DCIQZ42	NCIH2122	Investigative	[26]
Adenocarcinoma	DCYF3YD	NCIH23	Investigative	[26]
Adenocarcinoma	DC4NDC0	COLO320DM	Investigative	[26]
Adenocarcinoma	DC4X7RY	DLD1	Investigative	[26]
Adenocarcinoma	DCPG3V8	HT29	Investigative	[26]
Amelanotic melanoma	DCYYWX6	A2058	Investigative	[26]
Germ cell tumour	DCLA14V	PA1	Investigative	[26]
Hodgkin lymphoma	DC3OCBP	U-HO1	Investigative	[26]
Large cell lung carcinoma	DC51XGW	NCI-H460	Investigative	[26]
Malignant melanoma	DCPUCRG	RPMI7951	Investigative	[26]
Malignant melanoma	DCC6Q3J	UACC62	Investigative	[26]
Non small cell carcinoma	DCLL49C	SKMES1	Investigative	[26]
Ovarian endometrioid adenocarcinoma	DCYE2H2	A2780	Investigative	[26]
Ovarian serous cystadenocarcinoma	DCKEM2B	SK-OV-3	Investigative	[26]
Prostate carcinoma	DCCUPDI	LNCAP	Investigative	[26]
Breast and ovarian cancer syndrome	DCUGL3V	UWB1289	Investigative	[1]
Breast and ovarian cancer syndrome	DCEUWNY	UWB1289+BRCA1	Investigative	[1]
Breast carcinoma	DCBUNOQ	KPL1	Investigative	[1]
Carcinoma	DC0ZJLL	OV90	Investigative	[1]
Carcinoma	DCSWMN5	EFM192B	Investigative	[1]
Rectal adenocarcinoma	DCGKU9V	SW837	Investigative	[1]

References

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• [3] UBE2T promotes nasopharyngeal carcinoma cell proliferation, invasion, and metastasis by activating the AKT/GSK3/-catenin pathway.Oncotarget. 2016 Mar 22;7(12):15161-72.
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• [5] Chemerin promotes the pathogenesis of preeclampsia by activating CMKLR1/p-Akt/CEBP axis and inducing M1 macrophage polarization. Cell Biol Toxicol. 2022 Aug;38(4):611-628. doi: 10.1007/s10565-021-09636-7. Epub 2021 Aug 16.
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• [7] Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells. Sci Rep. 2016 Nov 29;6:37997. doi: 10.1038/srep37997.
• [8] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [9] PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. Toxicol Appl Pharmacol. 2019 Oct 15;381:114729. doi: 10.1016/j.taap.2019.114729. Epub 2019 Aug 22.
• [10] Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels. Oncotarget. 2012 Aug;3(8):811-23. doi: 10.18632/oncotarget.579.
• [11] -Mangostin alleviates liver fibrosis through Sirtuin 3-superoxide-high mobility group box 1 signaling axis. Toxicol Appl Pharmacol. 2019 Jan 15;363:142-153. doi: 10.1016/j.taap.2018.11.011. Epub 2018 Nov 29.
• [12] Akt activation by Ca(2+)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells. J Biol Chem. 2017 Aug 25;292(34):14188-14204. doi: 10.1074/jbc.M117.778464. Epub 2017 Jun 20.
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• [16] Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Lett. 2014 Jun 1;347(2):204-11. doi: 10.1016/j.canlet.2014.02.018. Epub 2014 Feb 24.
• [17] Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway. Toxicol In Vitro. 2020 Aug;66:104852. doi: 10.1016/j.tiv.2020.104852. Epub 2020 Apr 5.
• [18] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [19] Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance. Oncogene. 2012 May 10;31(19):2412-22. doi: 10.1038/onc.2011.426. Epub 2011 Sep 26.
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• [21] MEK inhibitor PD-0325901 overcomes resistance to CK2 inhibitor CX-4945 and exhibits anti-tumor activity in head and neck cancer. Int J Biol Sci. 2015 Feb 23;11(4):411-22. doi: 10.7150/ijbs.10745. eCollection 2015.
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• [24] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
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