Details of the Drug Combination

General Information of Drug Combination (ID: DCDY1H4)

• Drug Combination Name: Sirolimus + Chlorambucil
• Indication: Childhood T acute lymphoblastic leukemia; Status: Investigative [1]
• Component Drugs:
  Sirolimus (DMGW1ID): Small molecular drug
  Chlorambucil (DMRKE63): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CCRF-CEM
  Zero Interaction Potency (ZIP) Score: 1.17
  Bliss Independence Score: 1.57
  Loewe Additivity Score: 1.5
  LHighest Single Agent (HSA) Score: 4.37

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sirolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Brainstem neoplasm	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Lung lymphangioleiomyomatosis	N.A.	Approved	[2]
Lymphangioleiomyomatosis	CB07	Approved	[3]
Mucosal melanoma	N.A.	Approved	[2]
Multiple myeloma	2A83	Approved	[4]
Multiple sclerosis	8A40	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Organ transplant rejection	NE84	Approved	[5]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Uveitis	9A96.Z	Phase 3	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Dutch elm disease	8D64	Phase 1/2	[5]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Rheumatoid arthritis	FA20	Investigative	[2]

Sirolimus Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[10]
PI3K/AKT/mTOR pathway (PAm pathway)	TTGQUFK	NOUNIPROTAC	Inhibitor	[11]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[12]

Sirolimus Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[14]

Sirolimus Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]

Sirolimus Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[17]

Indication(s) of Chlorambucil

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[8]
Small lymphocytic lymphoma	2A82.0	Approved	[9]
Classic Hodgkin lymphoma	N.A.	Investigative	[9]
Follicular lymphoma	2A80	Investigative	[9]

Chlorambucil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA replication (DNA repli)	TTABD5E	NOUNIPROTAC	Intercalator	[18]

Chlorambucil Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[20]

Chlorambucil Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[21]

Chlorambucil Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[22]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Expression	[23]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Expression	[23]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[23]
F-box only protein 30 (FBXO30)	OTD1P6LA	FBX30_HUMAN	Decreases Expression	[23]
Histone chaperone ASF1A (ASF1A)	OT4S44GP	ASF1A_HUMAN	Decreases Expression	[23]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Affects Expression	[24]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[25]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Affects Expression	[26]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[27]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[28]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[29]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[30]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[25]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[31]
Histone H4 (H4C1)	OTB71W46	H4_HUMAN	Decreases Expression	[28]
kinase isozyme 4, mitochondrial (PDK4)	OTCMHMBZ	PDK4_HUMAN	Affects Expression	[32]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[26]
Fanconi anemia group G protein (FANCG)	OT7MC8TZ	FANCG_HUMAN	Increases Response To Substance	[33]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[34]
Fanconi anemia group C protein (FANCC)	OTTIDM3P	FANCC_HUMAN	Increases Response To Substance	[33]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Papillary renal cell carcinoma	DC2ZB4F	ACHN	Investigative	[1]
Amelanotic melanoma	DCHE2VZ	MDA-MB-435	Investigative	[35]

References

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• [2] Sirolimus FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 201578.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] 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: 6031).
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] ClinicalTrials.gov (NCT04341675) Sirolimus Treatment in Hospitalized Patients With COVID-19 Pneumonia. U.S. National Institutes of Health.
• [8] 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: 7143).
• [9] Chlorambucil FDA Label
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• [27] Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells. Blood. 1996 Sep 15;88(6):2172-82.
• [28] A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate. Cell Cycle. 2006 Jul;5(14):1537-48. doi: 10.4161/cc.5.14.2913. Epub 2006 Jul 17.
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• [35] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976