Details of the Drug Combination

General Information of Drug Combination (ID: DCX21OX)

Drug Combination Name
PD-0325901 MK-5108
Indication
Disease Entry Status REF
Germ cell tumour Investigative [1]
Component Drugs PD-0325901   DM27D4J MK-5108   DMFGYKS
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: PA1
Zero Interaction Potency (ZIP) Score: 6.83
Bliss Independence Score: 6.45
Loewe Additivity Score: 2.77
LHighest Single Agent (HSA) Score: 9.66

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 [5]
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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 [6]
Cytochrome P450 3A5 (CYP3A5) OTSXFBXB CP3A5_HUMAN Increases Expression [6]
Cytochrome P450 3A7 (CYP3A7) OTTCDHHM CP3A7_HUMAN Increases Expression [6]
Nuclear receptor subfamily 0 group B member 2 (NR0B2) OT7UVICX NR0B2_HUMAN Decreases Expression [6]
Toll-like receptor 4 (TLR4) OTP7ML3S TLR4_HUMAN Decreases Expression [4]
Neuropilin-1 (NRP1) OTCGULYV NRP1_HUMAN Decreases Expression [4]
T-box transcription factor TBX3 (TBX3) OTM64N7K TBX3_HUMAN Decreases Expression [4]
Protein sprouty homolog 2 (SPRY2) OTH0CRCZ SPY2_HUMAN Decreases Expression [4]
Leupaxin (LPXN) OTUNV3CK LPXN_HUMAN Decreases Expression [4]
PR domain zinc finger protein 1 (PRDM1) OTQLSVBS PRDM1_HUMAN Decreases Expression [4]
Slit homolog 2 protein (SLIT2) OTLS2RJ4 SLIT2_HUMAN Decreases Expression [4]
Tumor necrosis factor ligand superfamily member 15 (TNFSF15) OTNGA2BW TNF15_HUMAN Decreases Expression [4]
Integrin beta-like protein 1 (ITGBL1) OTJDHE17 ITGBL_HUMAN Decreases Expression [4]
Urokinase-type plasminogen activator (PLAU) OTX0QGKK UROK_HUMAN Decreases Expression [4]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Decreases Expression [4]
Interstitial collagenase (MMP1) OTI4I2V1 MMP1_HUMAN Decreases Expression [4]
Glycophorin-C (GYPC) OTOEDR7O GLPC_HUMAN Decreases Expression [4]
Growth-regulated alpha protein (CXCL1) OT3WCTZV GROA_HUMAN Decreases Expression [4]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Decreases Expression [4]
Tissue factor pathway inhibitor (TFPI) OTA0FX16 TFPI1_HUMAN Decreases Expression [4]
Mast/stem cell growth factor receptor Kit (KIT) OTHUY3VZ KIT_HUMAN Decreases Expression [4]
Aminopeptidase N (ANPEP) OTP3WYFD AMPN_HUMAN Decreases Expression [4]
Integrin alpha-2 (ITGA2) OTPFL017 ITA2_HUMAN Decreases Expression [4]
Protein-glutamine gamma-glutamyltransferase 2 (TGM2) OT6MFOWF TGM2_HUMAN Decreases Expression [4]
Pentraxin-related protein PTX3 (PTX3) OTPXHRKU PTX3_HUMAN Decreases Expression [4]
5-hydroxytryptamine receptor 7 (HTR7) OT44DEWB 5HT7R_HUMAN Decreases Expression [4]
Glutaredoxin-1 (GLRX) OT0QHTAR GLRX1_HUMAN Decreases Expression [4]
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2) OT3K7HY5 DHB2_HUMAN Decreases Expression [4]
ETS translocation variant 5 (ETV5) OTE2OBM4 ETV5_HUMAN Decreases Expression [4]
ETS translocation variant 4 (ETV4) OT8C98UZ ETV4_HUMAN Decreases Expression [4]
Transcription factor SOX-9 (SOX9) OTVDJFGN SOX9_HUMAN Decreases Expression [4]
ETS translocation variant 1 (ETV1) OT6PMJIK ETV1_HUMAN Decreases Expression [4]
Stanniocalcin-1 (STC1) OTGVVXYF STC1_HUMAN Decreases Expression [4]
Paired mesoderm homeobox protein 1 (PRRX1) OTTZK5G8 PRRX1_HUMAN Decreases Expression [4]
Epithelial membrane protein 1 (EMP1) OTSZHUHQ EMP1_HUMAN Decreases Expression [4]
Forkhead box protein G1 (FOXG1) OTAW57J4 FOXG1_HUMAN Decreases Expression [4]
ADP-ribosylation factor-like protein 4C (ARL4C) OTQ3QNNU ARL4C_HUMAN Decreases Expression [4]
Reelin (RELN) OTLKMW1O RELN_HUMAN Decreases Expression [4]
C-C motif chemokine 20 (CCL20) OTUCJY4N CCL20_HUMAN Decreases Expression [4]
A-kinase anchor protein 12 (AKAP12) OTCVRDDX AKA12_HUMAN Decreases Expression [4]
Urokinase plasminogen activator surface receptor (PLAUR) OTIRKKEQ UPAR_HUMAN Decreases Expression [4]
Dual specificity protein phosphatase 4 (DUSP4) OT6WAO12 DUS4_HUMAN Decreases Expression [4]
Semaphorin-3A (SEMA3A) OTQJSV7W SEM3A_HUMAN Decreases Expression [4]
Monocyte to macrophage differentiation factor (MMD) OTB5I4OC PAQRB_HUMAN Decreases Expression [4]
Syntaxin-1A (STX1A) OTSBUZB4 STX1A_HUMAN Decreases Expression [4]
Dual specificity protein phosphatase 6 (DUSP6) OT4H6RKW DUS6_HUMAN Decreases Expression [4]
Kinesin-like protein KIF24 (KIF24) OTJTA5V3 KIF24_HUMAN Decreases Expression [4]
Anoctamin-1 (ANO1) OTSREUNI ANO1_HUMAN Decreases Expression [4]
NADH-cytochrome b5 reductase 2 (CYB5R2) OTTLM7XN NB5R2_HUMAN Decreases Expression [4]
Dynamin-binding protein (DNMBP) OTMHH14H DNMBP_HUMAN Decreases Expression [4]
Sialic acid-binding Ig-like lectin 15 (SIGLEC15) OTON4K9S SIG15_HUMAN Decreases Expression [4]
UPF0606 protein KIAA1549L (KIAA1549L) OT80HUVY K154L_HUMAN Decreases Expression [4]
Neuron navigator 3 (NAV3) OT97M1TR NAV3_HUMAN Decreases Expression [4]
Dedicator of cytokinesis protein 4 (DOCK4) OTH3XY8B DOCK4_HUMAN Decreases Expression [4]
Transmembrane protein 156 (TMEM156) OTH7YJID TM156_HUMAN Decreases Expression [4]
Tribbles homolog 2 (TRIB2) OTHSX3MX TRIB2_HUMAN Decreases Expression [4]
Hyaluronan synthase 2 (HAS2) OTTD3PAL HYAS2_HUMAN Decreases Expression [4]
Neuronal cell adhesion molecule (NRCAM) OT80HHQ2 NRCAM_HUMAN Decreases Expression [4]
Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) OTB71I02 DCBD2_HUMAN Decreases Expression [4]
Formin-like protein 2 (FMNL2) OT9OVWCV FMNL2_HUMAN Decreases Expression [4]
Monoglyceride lipase (MGLL) OT5ES4IE MGLL_HUMAN Decreases Expression [4]
Paternally-expressed gene 3 protein (PEG3) OTHQW98S PEG3_HUMAN Decreases Expression [4]
Disintegrin and metalloproteinase domain-containing protein 19 (ADAM19) OTH88TXU ADA19_HUMAN Decreases Expression [4]
Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15) OTGMPVNR S6A15_HUMAN Decreases Expression [4]
Endothelial cell-specific molecule 1 (ESM1) OT331Y8V ESM1_HUMAN Decreases Expression [4]
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) OTW3T4B2 IRPL1_HUMAN Decreases Expression [4]
Neurotrimin (NTM) OTHF0UQU NTRI_HUMAN Decreases Expression [4]
Histone deacetylase 9 (HDAC9) OTO8O0LF HDAC9_HUMAN Decreases Expression [4]
Type 2 lactosamine alpha-2,3-sialyltransferase (ST3GAL6) OTB17Q43 SIA10_HUMAN Decreases Expression [4]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [7]
Forkhead box protein O3 (FOXO3) OTHXQG4P FOXO3_HUMAN Increases Expression [8]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Decreases Expression [9]
DNA excision repair protein ERCC-1 (ERCC1) OTNPYQHI ERCC1_HUMAN Decreases Expression [10]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [11]
Fos-related antigen 1 (FOSL1) OT9YTYMB FOSL1_HUMAN Decreases Expression [12]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [13]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [13]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Increases Phosphorylation [11]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [14]
Heat shock factor protein 1 (HSF1) OTYNJ4KP HSF1_HUMAN Decreases Activity [15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Decreases Expression [7]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [11]
DNA repair endonuclease XPF (ERCC4) OTFIOPG1 XPF_HUMAN Increases Expression [10]
Ras-related C3 botulinum toxin substrate 1 (RAC1) OTKRO61U RAC1_HUMAN Affects Response To Substance [16]
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⏷ Show the Full List of 84 DOT(s)
Indication(s) of MK-5108
Disease Entry ICD 11 Status REF
Solid tumour/cancer 2A00-2F9Z Phase 1 [3]
MK-5108 Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Aurora kinase B (AURKB) TT5LS6T AURKB_HUMAN Inhibitor [17]
Aurora kinase A (AURKA) TTPS3C0 AURKA_HUMAN Inhibitor [17]
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Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour DCP1163 ES2 Investigative [18]
Breast carcinoma DCL0UVU KPL1 Investigative [19]
Breast carcinoma DCZ63ZD OCUBM Investigative [19]
Carcinoma DC9H9ZR EFM192B Investigative [19]
Carcinoma DC13JAN MDAMB436 Investigative [19]
Invasive ductal carcinoma DCPK3XK T-47D Investigative [19]
Adenocarcinoma DC4VG20 CAOV3 Investigative [1]
Adenocarcinoma DCLIQTL A427 Investigative [1]
Adenocarcinoma DC2BD8G NCIH520 Investigative [1]
Adenocarcinoma DC6X43X COLO320DM Investigative [1]
Adenocarcinoma DCLPDB2 DLD1 Investigative [1]
Malignant melanoma DCRABSY HT144 Investigative [1]
Malignant melanoma DCMELQV RPMI7951 Investigative [1]
Malignant melanoma DC6KJQX UACC62 Investigative [1]
Mesothelioma DCQ8YCC MSTO Investigative [1]
Ovarian endometrioid adenocarcinoma DCHTKG1 A2780 Investigative [1]
Prostate carcinoma DCE0KO9 LNCAP Investigative [1]
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⏷ Show the Full List of 17 DrugCom(s)

References

1 Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
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: 7935).
3 ClinicalTrials.gov (NCT00543387) Treatment of Participants With Advanced and/or Refractory Solid Tumors (MK-5108-001 AM4). U.S. National Institutes of Health.
4 PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
5 MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.
6 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.
7 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.
8 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.
9 Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
10 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.
11 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.
12 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.
13 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.
14 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.
15 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.
16 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.
17 A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
18 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.
19 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.