Details of the Drug Combination

General Information of Drug Combination (ID: DCAIQR2)

• Drug Combination Name: SCH 727965 + 10-hydroxycamptothecin
• Indication: Mesothelioma; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  10-hydroxycamptothecin (DM9WLN4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MSTO
  Zero Interaction Potency (ZIP) Score: 12.95
  Bliss Independence Score: 12.9
  Loewe Additivity Score: 9.02
  LHighest Single Agent (HSA) Score: 19.95

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	[4]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[4]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[4]

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	[5]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[5]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[6]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[6]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[6]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[6]

Indication(s) of 10-hydroxycamptothecin

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[3]

10-hydroxycamptothecin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase I (TOP1)	TTGTQHC	TOP1_HUMAN	Inhibitor	[3]

10-hydroxycamptothecin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[7]

10-hydroxycamptothecin Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Response To Substance	[8]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Affects Response To Substance	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Response To Substance	[8]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCIKU5O	ES2	Investigative	[10]
Breast carcinoma	DCS7S2U	KPL1	Investigative	[11]
Breast carcinoma	DCL7Y0G	OCUBM	Investigative	[11]
Carcinoma	DC5ECRN	EFM192B	Investigative	[11]
Colon adenocarcinoma	DCQB9JS	LOVO	Investigative	[11]
Colon carcinoma	DC1GXW1	RKO	Investigative	[11]
Adenocarcinoma	DCSEVUH	CAOV3	Investigative	[1]
Adenocarcinoma	DCPB73B	OVCAR3	Investigative	[1]
Adenocarcinoma	DCDZPOW	A427	Investigative	[1]
Adenocarcinoma	DCPGCMQ	NCIH1650	Investigative	[1]
Adenocarcinoma	DCKD99J	NCIH23	Investigative	[1]
Adenocarcinoma	DCL5PPA	NCIH520	Investigative	[1]
Adenocarcinoma	DCGV8E7	COLO320DM	Investigative	[1]
Adenocarcinoma	DC3P7GW	DLD1	Investigative	[1]
Adenocarcinoma	DCRJ5AZ	HCT116	Investigative	[1]
Adenocarcinoma	DCX2HO7	HT29	Investigative	[1]
Adenocarcinoma	DCLEAIF	SW-620	Investigative	[1]
Amelanotic melanoma	DCYL316	A2058	Investigative	[1]
Germ cell tumour	DC4S44I	PA1	Investigative	[1]
Large cell lung carcinoma	DC7OTQE	NCI-H460	Investigative	[1]
Malignant melanoma	DC92FJ5	A375	Investigative	[1]
Malignant melanoma	DCH1QF2	RPMI7951	Investigative	[1]
Malignant melanoma	DCNH31A	SKMEL30	Investigative	[1]
Malignant melanoma	DCJVISE	UACC62	Investigative	[1]
Non small cell carcinoma	DCRAIJC	SKMES1	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCCZBWU	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DC5BUZQ	SK-OV-3	Investigative	[1]
Prostate carcinoma	DCK8T8X	LNCAP	Investigative	[1]
Prostate carcinoma	DCJ3JPL	VCAP	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] Upregulation of p21WAF1/CIP1 in human breast cancer cell lines MCF-7 and MDA-MB-468 undergoing apoptosis induced by natural product anticancer drugs 10-hydroxycamptothecin and camptothecin through p53-dependent and independent pathways. Int J Oncol. 1998 Apr;12(4):793-804.
• [4] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [5] 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.
• [6] 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.
• [7] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [8] siRNA-mediated Bcl-2 and Bcl-xl gene silencing sensitizes human hepatoblastoma cells to chemotherapeutic drugs. Clin Exp Pharmacol Physiol. 2007 May-Jun;34(5-6):450-6. doi: 10.1111/j.1440-1681.2007.04593.x.
• [9] Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11636-41. doi: 10.1073/pnas.1934692100. Epub 2003 Sep 16.
• [10] 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.
• [11] 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.