Details of the Drug Combination

General Information of Drug Combination (ID: DC1BFOC)

• Drug Combination Name: SCH 727965 + AS602868
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  AS602868 (DMKXDOI): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SU-DIPG-XIII
  Zero Interaction Potency (ZIP) Score: 3.058
  Bliss Independence Score: 3.425
  Loewe Additivity Score: 0.061
  LHighest Single Agent (HSA) Score: 0.154

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 AS602868

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Discontinued in Phase 1	[3]

AS602868 Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase type B (MAO-B)	TTGP7BY	AOFB_HUMAN	Inhibitor	[7]
Nuclear factor NF-kappa-B (NFKB)	TTSXVID	NFKB1_HUMAN; NFKB2_HUMAN; TF65_HUMAN; RELB_HUMAN; REL_HUMAN	Inhibitor	[8]
Monoamine oxidase type A (MAO-A)	TT3WG5C	AOFA_HUMAN	Inhibitor	[7]

AS602868 Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[9]

References

• [1] 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.
• [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] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009941)
• [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] Inhibition of rat brain monoamine oxidase activities by psoralen and isopsoralen: implications for the treatment of affective disorders. Pharmacol Toxicol. 2001 Feb;88(2):75-80.
• [8] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [9] Pharmacological targeting of NF-kappaB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells. Br J Cancer. 2008 Jan 29;98(2):335-44. doi: 10.1038/sj.bjc.6604082. Epub 2008 Jan 8.