Details of the Drug Combination

General Information of Drug Combination (ID: DCM1EIT)

• Drug Combination Name: SCH 727965 + CYTISINE
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  CYTISINE (DMUF0BJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SU-DIPG-XIII
  Zero Interaction Potency (ZIP) Score: 20.97
  Bliss Independence Score: 21.696
  Loewe Additivity Score: 7.948
  LHighest Single Agent (HSA) Score: 8.013

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 CYTISINE

Disease Entry	ICD 11	Status	REF
Tobacco dependence	6C4A.2	Phase 3	[3]

CYTISINE Interacts with 6 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Neuronal acetylcholine receptor alpha-7 (CHRNA7)	TTLA931	ACHA7_HUMAN	Inhibitor	[7]
Neuronal acetylcholine receptor alpha-2 (CHRNA2)	TTF4E0J	ACHA2_HUMAN	Inhibitor	[8]
Neuronal acetylcholine receptor alpha-4 (CHRNA4)	TT4H1MQ	ACHA4_HUMAN	Inhibitor	[9]
Neuronal acetylcholine receptor beta-4 (CHRNB4)	TTTVAFQ	ACHB4_HUMAN	Inhibitor	[10]
Nicotinic acetylcholine receptor (nAChR)	TTJSZTB	NOUNIPROTAC	Antagonist	[3]
Neuronal acetylcholine receptor beta-2 (CHRNB2)	TT5KPZR	ACHB2_HUMAN	Inhibitor	[9]

CYTISINE Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Neuronal acetylcholine receptor subunit alpha-4 (CHRNA4)	OT1H0ZXC	ACHA4_HUMAN	Affects Binding	[11]
Neuronal acetylcholine receptor subunit beta-2 (CHRNB2)	OTNAT2M5	ACHB2_HUMAN	Affects Binding	[11]

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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4889-97.
• [8] Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity. J Med Chem. 2006 May 4;49(9):2673-6.
• [9] Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7.
• [10] Deconstructing cytisine: The syntheses of (+/-)-cyfusine and (+/-)-cyclopropylcyfusine, fused ring analogs of cytisine. Bioorg Med Chem Lett. 2008 Apr 1;18(7):2316-9.
• [11] ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. J Pharmacol Exp Ther. 1997 Oct;283(1):235-46.