General Information of Drug Combination (ID: DC4ZF58)

Drug Combination Name
PD-0325901 MK-2206
Indication
Disease Entry Status REF
Amelanotic melanoma Investigative [1]
Component Drugs PD-0325901   DM27D4J MK-2206   DMT1OZ6
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: A2058
Zero Interaction Potency (ZIP) Score: 4.55
Bliss Independence Score: 8.25
Loewe Additivity Score: 7.54
LHighest Single Agent (HSA) Score: 11.85

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of PD-0325901
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Phase 2 [2]
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 [6]
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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 [7]
Cytochrome P450 3A5 (CYP3A5) OTSXFBXB CP3A5_HUMAN Increases Expression [7]
Cytochrome P450 3A7 (CYP3A7) OTTCDHHM CP3A7_HUMAN Increases Expression [7]
Nuclear receptor subfamily 0 group B member 2 (NR0B2) OT7UVICX NR0B2_HUMAN Decreases Expression [7]
Toll-like receptor 4 (TLR4) OTP7ML3S TLR4_HUMAN Decreases Expression [5]
Neuropilin-1 (NRP1) OTCGULYV NRP1_HUMAN Decreases Expression [5]
T-box transcription factor TBX3 (TBX3) OTM64N7K TBX3_HUMAN Decreases Expression [5]
Protein sprouty homolog 2 (SPRY2) OTH0CRCZ SPY2_HUMAN Decreases Expression [5]
Leupaxin (LPXN) OTUNV3CK LPXN_HUMAN Decreases Expression [5]
PR domain zinc finger protein 1 (PRDM1) OTQLSVBS PRDM1_HUMAN Decreases Expression [5]
Slit homolog 2 protein (SLIT2) OTLS2RJ4 SLIT2_HUMAN Decreases Expression [5]
Tumor necrosis factor ligand superfamily member 15 (TNFSF15) OTNGA2BW TNF15_HUMAN Decreases Expression [5]
Integrin beta-like protein 1 (ITGBL1) OTJDHE17 ITGBL_HUMAN Decreases Expression [5]
Urokinase-type plasminogen activator (PLAU) OTX0QGKK UROK_HUMAN Decreases Expression [5]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Decreases Expression [5]
Interstitial collagenase (MMP1) OTI4I2V1 MMP1_HUMAN Decreases Expression [5]
Glycophorin-C (GYPC) OTOEDR7O GLPC_HUMAN Decreases Expression [5]
Growth-regulated alpha protein (CXCL1) OT3WCTZV GROA_HUMAN Decreases Expression [5]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Decreases Expression [5]
Tissue factor pathway inhibitor (TFPI) OTA0FX16 TFPI1_HUMAN Decreases Expression [5]
Mast/stem cell growth factor receptor Kit (KIT) OTHUY3VZ KIT_HUMAN Decreases Expression [5]
Aminopeptidase N (ANPEP) OTP3WYFD AMPN_HUMAN Decreases Expression [5]
Integrin alpha-2 (ITGA2) OTPFL017 ITA2_HUMAN Decreases Expression [5]
Protein-glutamine gamma-glutamyltransferase 2 (TGM2) OT6MFOWF TGM2_HUMAN Decreases Expression [5]
Pentraxin-related protein PTX3 (PTX3) OTPXHRKU PTX3_HUMAN Decreases Expression [5]
5-hydroxytryptamine receptor 7 (HTR7) OT44DEWB 5HT7R_HUMAN Decreases Expression [5]
Glutaredoxin-1 (GLRX) OT0QHTAR GLRX1_HUMAN Decreases Expression [5]
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2) OT3K7HY5 DHB2_HUMAN Decreases Expression [5]
ETS translocation variant 5 (ETV5) OTE2OBM4 ETV5_HUMAN Decreases Expression [5]
ETS translocation variant 4 (ETV4) OT8C98UZ ETV4_HUMAN Decreases Expression [5]
Transcription factor SOX-9 (SOX9) OTVDJFGN SOX9_HUMAN Decreases Expression [5]
ETS translocation variant 1 (ETV1) OT6PMJIK ETV1_HUMAN Decreases Expression [5]
Stanniocalcin-1 (STC1) OTGVVXYF STC1_HUMAN Decreases Expression [5]
Paired mesoderm homeobox protein 1 (PRRX1) OTTZK5G8 PRRX1_HUMAN Decreases Expression [5]
Epithelial membrane protein 1 (EMP1) OTSZHUHQ EMP1_HUMAN Decreases Expression [5]
Forkhead box protein G1 (FOXG1) OTAW57J4 FOXG1_HUMAN Decreases Expression [5]
ADP-ribosylation factor-like protein 4C (ARL4C) OTQ3QNNU ARL4C_HUMAN Decreases Expression [5]
Reelin (RELN) OTLKMW1O RELN_HUMAN Decreases Expression [5]
C-C motif chemokine 20 (CCL20) OTUCJY4N CCL20_HUMAN Decreases Expression [5]
A-kinase anchor protein 12 (AKAP12) OTCVRDDX AKA12_HUMAN Decreases Expression [5]
Urokinase plasminogen activator surface receptor (PLAUR) OTIRKKEQ UPAR_HUMAN Decreases Expression [5]
Dual specificity protein phosphatase 4 (DUSP4) OT6WAO12 DUS4_HUMAN Decreases Expression [5]
Semaphorin-3A (SEMA3A) OTQJSV7W SEM3A_HUMAN Decreases Expression [5]
Monocyte to macrophage differentiation factor (MMD) OTB5I4OC PAQRB_HUMAN Decreases Expression [5]
Syntaxin-1A (STX1A) OTSBUZB4 STX1A_HUMAN Decreases Expression [5]
Dual specificity protein phosphatase 6 (DUSP6) OT4H6RKW DUS6_HUMAN Decreases Expression [5]
Kinesin-like protein KIF24 (KIF24) OTJTA5V3 KIF24_HUMAN Decreases Expression [5]
Anoctamin-1 (ANO1) OTSREUNI ANO1_HUMAN Decreases Expression [5]
NADH-cytochrome b5 reductase 2 (CYB5R2) OTTLM7XN NB5R2_HUMAN Decreases Expression [5]
Dynamin-binding protein (DNMBP) OTMHH14H DNMBP_HUMAN Decreases Expression [5]
Sialic acid-binding Ig-like lectin 15 (SIGLEC15) OTON4K9S SIG15_HUMAN Decreases Expression [5]
UPF0606 protein KIAA1549L (KIAA1549L) OT80HUVY K154L_HUMAN Decreases Expression [5]
Neuron navigator 3 (NAV3) OT97M1TR NAV3_HUMAN Decreases Expression [5]
Dedicator of cytokinesis protein 4 (DOCK4) OTH3XY8B DOCK4_HUMAN Decreases Expression [5]
Transmembrane protein 156 (TMEM156) OTH7YJID TM156_HUMAN Decreases Expression [5]
Tribbles homolog 2 (TRIB2) OTHSX3MX TRIB2_HUMAN Decreases Expression [5]
Hyaluronan synthase 2 (HAS2) OTTD3PAL HYAS2_HUMAN Decreases Expression [5]
Neuronal cell adhesion molecule (NRCAM) OT80HHQ2 NRCAM_HUMAN Decreases Expression [5]
Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) OTB71I02 DCBD2_HUMAN Decreases Expression [5]
Formin-like protein 2 (FMNL2) OT9OVWCV FMNL2_HUMAN Decreases Expression [5]
Monoglyceride lipase (MGLL) OT5ES4IE MGLL_HUMAN Decreases Expression [5]
Paternally-expressed gene 3 protein (PEG3) OTHQW98S PEG3_HUMAN Decreases Expression [5]
Disintegrin and metalloproteinase domain-containing protein 19 (ADAM19) OTH88TXU ADA19_HUMAN Decreases Expression [5]
Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15) OTGMPVNR S6A15_HUMAN Decreases Expression [5]
Endothelial cell-specific molecule 1 (ESM1) OT331Y8V ESM1_HUMAN Decreases Expression [5]
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) OTW3T4B2 IRPL1_HUMAN Decreases Expression [5]
Neurotrimin (NTM) OTHF0UQU NTRI_HUMAN Decreases Expression [5]
Histone deacetylase 9 (HDAC9) OTO8O0LF HDAC9_HUMAN Decreases Expression [5]
Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6) OTB17Q43 SIA10_HUMAN Decreases Expression [5]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [8]
Forkhead box protein O3 (FOXO3) OTHXQG4P FOXO3_HUMAN Increases Expression [9]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Decreases Expression [10]
DNA excision repair protein ERCC-1 (ERCC1) OTNPYQHI ERCC1_HUMAN Decreases Expression [11]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [12]
Fos-related antigen 1 (FOSL1) OT9YTYMB FOSL1_HUMAN Decreases Expression [13]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [14]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [14]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Increases Phosphorylation [12]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [15]
Heat shock factor protein 1 (HSF1) OTYNJ4KP HSF1_HUMAN Decreases Activity [16]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Decreases Expression [8]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [12]
DNA repair endonuclease XPF (ERCC4) OTFIOPG1 XPF_HUMAN Increases Expression [11]
Ras-related C3 botulinum toxin substrate 1 (RAC1) OTKRO61U RAC1_HUMAN Affects Response To Substance [17]
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⏷ Show the Full List of 84 DOT(s)
Indication(s) of MK-2206
Disease Entry ICD 11 Status REF
Rectal adenocarcinoma 2B92 Phase 2 [3]
Nasopharyngeal carcinoma 2B6B Investigative [4]
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 [19]
E2 ubiquitin-conjugating enzyme T (UBE2T) TT0A1R8 UBE2T_HUMAN Inhibitor [4]
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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 [20]
Tumor necrosis factor (TNF) OT4IE164 TNFA_HUMAN Decreases Secretion [18]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Increases Expression [20]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Decreases Secretion [18]
Endothelin-1 (EDN1) OTZCACEG EDN1_HUMAN Decreases Expression [18]
Tissue factor (F3) OT3MSU3B TF_HUMAN Increases Expression [21]
Vascular endothelial growth factor receptor 1 (FLT1) OTT0OGYS VGFR1_HUMAN Decreases Expression [18]
Interleukin-10 (IL10) OTIRFRXC IL10_HUMAN Increases Secretion [18]
Endothelin receptor type B (EDNRB) OTLLZV3P EDNRB_HUMAN Increases Expression [18]
Tumor necrosis factor receptor superfamily member 6 (FAS) OTP9XG86 TNR6_HUMAN Affects Response To Substance [22]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Phosphorylation [23]
T-lymphocyte activation antigen CD80 (CD80) OTJBLUQE CD80_HUMAN Decreases Expression [18]
T-lymphocyte activation antigen CD86 (CD86) OTJCSBPC CD86_HUMAN Decreases Expression [18]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Cleavage [23]
CCAAT/enhancer-binding protein alpha (CEBPA) OTOM9OE4 CEBPA_HUMAN Decreases Expression [18]
Actin, aortic smooth muscle (ACTA2) OTEDLG8E ACTA_HUMAN Decreases Expression [24]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [23]
Interferon regulatory factor 8 (IRF8) OT8YSNI4 IRF8_HUMAN Decreases Expression [18]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) OTHBQVD5 4EBP1_HUMAN Decreases Phosphorylation [23]
Proline-rich AKT1 substrate 1 (AKT1S1) OT4JHN4Y AKTS1_HUMAN Decreases Phosphorylation [25]
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⏷ Show the Full List of 20 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Breast and ovarian cancer syndrome DC6ED9P UWB1289 Investigative [26]
Breast carcinoma DCNQ1T8 KPL1 Investigative [26]
Breast carcinoma DCGL1QF OCUBM Investigative [26]
Carcinoma DCPW344 OV90 Investigative [26]
Carcinoma DCQROCU EFM192B Investigative [26]
Carcinoma DCYHVE4 MDAMB436 Investigative [26]
Colon carcinoma DCIQZ0R RKO Investigative [26]
Invasive ductal carcinoma DC1LZNS T-47D Investigative [26]
Rectal adenocarcinoma DC69JPT SW837 Investigative [26]
Adenocarcinoma DC7UTM2 OVCAR3 Investigative [1]
Adenocarcinoma DCFWLG9 A427 Investigative [1]
Adenocarcinoma DCLHADZ NCIH1650 Investigative [1]
Adenocarcinoma DCDI39N NCIH2122 Investigative [1]
Adenocarcinoma DCNG2LD NCIH520 Investigative [1]
Adenocarcinoma DCLWN16 NCIH23 Investigative [1]
Adenocarcinoma DCAMEBC COLO320DM Investigative [1]
Adenocarcinoma DCR6BA2 DLD1 Investigative [1]
Adenocarcinoma DCH56PU HT29 Investigative [1]
Large cell lung carcinoma DCI0R4X NCI-H460 Investigative [1]
Malignant melanoma DCL7I0X RPMI7951 Investigative [1]
Malignant melanoma DC8URF5 UACC62 Investigative [1]
Mesothelioma DCR3YSO MSTO Investigative [1]
Non small cell carcinoma DCZ8EPL SKMES1 Investigative [1]
Ovarian endometrioid adenocarcinoma DCYSXLR A2780 Investigative [1]
Ovarian serous cystadenocarcinoma DC4UPC5 SK-OV-3 Investigative [1]
Prostate carcinoma DCJUY1E VCAP Investigative [1]
Prostate carcinoma DC5LJRR LNCAP Investigative [1]
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⏷ Show the Full List of 27 DrugCom(s)

References

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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: 7945).
4 UBE2T promotes nasopharyngeal carcinoma cell proliferation, invasion, and metastasis by activating the AKT/GSK3/-catenin pathway.Oncotarget. 2016 Mar 22;7(12):15161-72.
5 PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
6 MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.
7 U0126, a mitogen-activated protein kinase kinase 1 and 2 (MEK1 and 2) inhibitor, selectively up-regulates main isoforms of CYP3A subfamily via a pregnane X receptor (PXR) in HepG2 cells. Arch Toxicol. 2014 Dec;88(12):2243-59.
8 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.
9 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.
10 Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
11 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.
12 Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras. Oncotarget. 2016 Oct 25;7(43):69804-69815. doi: 10.18632/oncotarget.12001.
13 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.
14 The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br J Cancer. 2012 Apr 10;106(8):1386-94. doi: 10.1038/bjc.2012.70. Epub 2012 Mar 13.
15 Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur J Cancer. 2013 Dec;49(18):3936-44. doi: 10.1016/j.ejca.2013.08.007. Epub 2013 Sep 3.
16 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.
17 Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res. 2012 Dec;22(12):2315-27. doi: 10.1101/gr.140988.112. Epub 2012 Oct 2.
18 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.
19 First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors.J Clin Oncol.2011 Dec 10;29(35):4688-95.
20 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.
21 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.
22 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.
23 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.
24 -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.
25 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.
26 Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.