Details of the Drug Combination

General Information of Drug Combination (ID: DCW2NC9)

• Drug Combination Name: SCH 727965 + Valrubicin
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  Valrubicin (DMOYJFK): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HCT-15
  Zero Interaction Potency (ZIP) Score: 7
  Bliss Independence Score: 7.62
  Loewe Additivity Score: 8.26
  LHighest Single Agent (HSA) Score: 9.66

Molecular Interaction Atlas of This Drug Combination

Indication(s) of SCH 727965

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

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	[6]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[6]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[6]

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	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[7]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[8]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[8]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[8]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[8]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[8]

Indication(s) of Valrubicin

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[3]
In situ carcinoma	N.A.	Approved	[4]
Urinary bladder cancer	N.A.	Approved	[4]
Psoriasis vulgaris	EA90	Phase 2	[5]

Valrubicin 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	Inhibitor	[9]

Valrubicin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[10]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DC3ECH3	HL-60(TB)	Investigative	[11]
Anaplastic large cell lymphoma	DC0CBU4	SR	Investigative	[11]
Astrocytoma	DCC1JXJ	U251	Investigative	[11]
Astrocytoma	DC2Z4XG	SNB-19	Investigative	[11]
Clear cell renal cell carcinoma	DC7IJ0V	786-0	Investigative	[11]
Clear cell renal cell carcinoma	DCPXMZ9	A498	Investigative	[11]
Clear cell renal cell carcinoma	DC4QHED	CAKI-1	Investigative	[11]
Glioblastoma	DCM1H33	SNB-75	Investigative	[11]
Glioma	DCCXNR5	SF-539	Investigative	[11]
Papillary renal cell carcinoma	DC74M4D	ACHN	Investigative	[11]
Plasma cell myeloma	DC7AHQP	RPMI-8226	Investigative	[11]
Renal cell carcinoma	DC52B8U	SN12C	Investigative	[11]
Renal cell carcinoma	DCZSYQ0	UO-31	Investigative	[11]
Carcinoma	DCKVWFQ	RXF 393	Investigative	[12]
Colon adenocarcinoma	DCTBWQQ	COLO 205	Investigative	[12]
Colon carcinoma	DC6A5AC	KM12	Investigative	[12]
Invasive ductal carcinoma	DCZTHPL	HS 578T	Investigative	[12]
Adenocarcinoma	DC5MKNF	DU-145	Investigative	[1]
Adenocarcinoma	DC2HNV6	OVCAR3	Investigative	[1]
Adenocarcinoma	DCKBY92	NCIH23	Investigative	[1]
Adenocarcinoma	DCYOP9S	SW-620	Investigative	[1]
Adenocarcinoma	DCR7ES1	HT29	Investigative	[1]
Amelanotic melanoma	DC6U5RO	MDA-MB-435	Investigative	[1]
Amelanotic melanoma	DCDTD20	M14	Investigative	[1]
Cutaneous melanoma	DCCO3KL	SK-MEL-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC4B7EZ	OVCAR-4	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCEMDPV	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCXET5M	OVCAR-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCL0QJR	NCI\\/ADR-RES	Investigative	[1]
Large cell lung carcinoma	DCJ9X6E	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DCKIRZX	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DCRAVKK	EKVX	Investigative	[1]
Lung adenocarcinoma	DC58857	HOP-62	Investigative	[1]
Lung adenocarcinoma	DCK864R	NCI-H522	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCVR6RL	NCI-H322M	Investigative	[1]
Non-small cell lung carcinoma	DCNGAI7	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCI6KVJ	SK-OV-3	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] 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).
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Valrubicin FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [7] 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.
• [8] 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.
• [9] Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5.
• [10] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [11] 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.
• [12] 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.