Details of the Drug Combination

General Information of Drug Combination (ID: DCY06NZ)

• Drug Combination Name: Vinorelbine + SCH 727965
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  Vinorelbine (DMVXFYE): Small molecular drug
  SCH 727965 (DMCJLD1): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: RPMI7951
  Zero Interaction Potency (ZIP) Score: 4.3
  Bliss Independence Score: 0.76
  Loewe Additivity Score: 44.31
  LHighest Single Agent (HSA) Score: 1.06

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vinorelbine

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Approved	[3]

Vinorelbine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin (TUB)	TTML2WA	NOUNIPROTAC	Inhibitor	[5]

Vinorelbine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Vinorelbine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]

Vinorelbine Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[9]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Expression	[9]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[10]
Vitamin K-dependent protein C (PROC)	OTGVH484	PROC_HUMAN	Decreases Expression	[11]
Keratin, type I cytoskeletal 18 (KRT18)	OTVLQFIP	K1C18_HUMAN	Increases Expression	[12]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Increases Expression	[13]
Splicing factor 45 (RBM17)	OT9ROJCL	SPF45_HUMAN	Decreases Response To Substance	[14]
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Affects Response To Substance	[15]
Nucleophosmin (NPM1)	OTTBYYT0	NPM_HUMAN	Decreases Response To Substance	[16]

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[4]

SCH 727965 Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 9 (CDK9)	TT1LVF2	CDK9_HUMAN	Inhibitor	[17]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[17]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[17]

SCH 727965 Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[18]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[18]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[19]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[19]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[19]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[19]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Colon adenocarcinoma	DC0O6X1	LOVO	Investigative	[20]
Adenocarcinoma	DCCMQQZ	A427	Investigative	[1]
Adenocarcinoma	DCNBJRW	NCIH520	Investigative	[1]
Adenocarcinoma	DCCUNL4	COLO320DM	Investigative	[1]
Adenocarcinoma	DCBEWOB	DLD1	Investigative	[1]
Adenocarcinoma	DCOW3J3	HCT116	Investigative	[1]
Adenocarcinoma	DCRSOJG	HT29	Investigative	[1]
Adenocarcinoma	DC4LVEK	SW-620	Investigative	[1]
Amelanotic melanoma	DCBCKZS	A2058	Investigative	[1]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DC714VI	ES2	Investigative	[1]
Germ cell tumour	DC0QSSE	PA1	Investigative	[1]
Large cell lung carcinoma	DCGLC5I	NCI-H460	Investigative	[1]
Malignant melanoma	DCY8VA3	A375	Investigative	[1]
Malignant melanoma	DCIPEG6	SKMEL30	Investigative	[1]
Non small cell carcinoma	DC8252D	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCJ5M0G	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCYZD7L	SK-OV-3	Investigative	[1]
Prostate carcinoma	DCT5WTM	LNCAP	Investigative	[1]

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] Vinorelbine FDA Label
• [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: 7105).
• [4] 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: 7379).
• [5] Vinca alkaloid and MDR1. Gan To Kagaku Ryoho. 2008 Jul;35(7):1086-9.
• [6] Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8.
• [7] Characterization of human cytochrome P450 isoenzymes involved in the metabolism of vinorelbine. Fundam Clin Pharmacol. 2005 Oct;19(5):545-53.
• [8] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [9] Effects of capecitabine and vinorelbine on cell proliferation, metabolism and COX2 and p16 expression in breast cancer cell lines and solid tumour tissues. Biomed Pharmacother. 2007 Oct;61(9):596-600.
• [10] Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
• [11] Acquired protein C deficiency following cisplatinum-navelbine administration for locally advanced breast cancer. Case report. Eur J Gynaecol Oncol. 1999;20(4):323-4.
• [12] Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer. 2006 Jun 5;94(11):1592-8. doi: 10.1038/sj.bjc.6603129.
• [13] Adenocarcinoma cells exposed in vitro to Navelbine or Taxol increase Ep-CAM expression through a novel mechanism. Cancer Immunol Immunother. 2003 Jul;52(7):429-37. doi: 10.1007/s00262-003-0386-7. Epub 2003 Apr 15.
• [14] Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res. 2005 Aug 1;65(15):6593-600. doi: 10.1158/0008-5472.CAN-03-3675.
• [15] High expression of nucleoside transporter protein hENT1 in Reed-Sternberg cells is associated with treatment failure in relapsed/refractory Hodgkin lymphoma patients treated with gemcitabine, vinorelbine and liposomal doxorubicin - a CALGB 59804 correlative study. Leuk Lymphoma. 2008 Jun;49(6):1202-5. doi: 10.1080/10428190802094237.
• [16] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [17] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [18] Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
• [19] CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
• [20] 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.