Details of the Drug Combination

General Information of Drug Combination (ID: DCUI17H)

• Drug Combination Name: Bafilomycin A1 + LY2835219
• Indication: Diffuse intrinsic pontine glioma; Status: Investigative [1]
• Component Drugs:
  Bafilomycin A1 (DMUNK59): Small molecular drug
  LY2835219 (DM93VBZ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: DIPG25
  Zero Interaction Potency (ZIP) Score: 6.82
  Bliss Independence Score: 9.72
  Loewe Additivity Score: 2.37
  LHighest Single Agent (HSA) Score: 3.68

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bafilomycin A1

Disease Entry	ICD 11	Status	REF
B-cell acute lymphoblastic leukaemia	2B33.3	Investigative	[2]

Bafilomycin A1 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vacuolar-type proton ATPase (v-ATPase)	TTTK3BH	NOUNIPROTAC	Inhibitor	[6]

Bafilomycin A1 Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptotic protease-activating factor 1 (APAF1)	OTJWIVY0	APAF_HUMAN	Increases Expression	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Expression	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Expression	[7]
Steroidogenic factor 1 (NR5A1)	OTOULYR4	STF1_HUMAN	Decreases Expression	[8]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[5]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Uptake	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[10]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Increases Expression	[11]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[12]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[13]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[5]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Cleavage	[14]
Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A)	OTPMGIU4	MLP3A_HUMAN	Increases Expression	[15]
Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2)	OTLS7C99	LRRK2_HUMAN	Increases Response To Substance	[16]

Indication(s) of LY2835219

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[3]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[4]

LY2835219 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 4 (CDK4)	TT0PG8F	CDK4_HUMAN	Modulator	[18]
Cyclin-dependent kinase 6 (CDK6)	TTO0FDJ	CDK6_HUMAN	Modulator	[18]

LY2835219 Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[19]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[19]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[19]

LY2835219 Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]

LY2835219 Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutaminase kidney isoform, mitochondrial (GLS)	OTGOZG2M	GLSK_HUMAN	Increases Expression	[17]
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[17]
Securin (PTTG1)	OTIMYS4W	PTTG1_HUMAN	Decreases Expression	[17]
Fibrinogen beta chain (FGB)	OT6RKLI9	FIBB_HUMAN	Decreases Expression	[17]
Fibrinogen gamma chain (FGG)	OT5BJSEX	FIBG_HUMAN	Decreases Expression	[17]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[21]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[22]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[17]
SPARC (SPARC)	OTPN90H0	SPRC_HUMAN	Increases Expression	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[17]
Ran-specific GTPase-activating protein (RANBP1)	OTQE226K	RANG_HUMAN	Decreases Expression	[17]
Ephrin-B3 (EFNB3)	OT12WTXQ	EFNB3_HUMAN	Decreases Expression	[17]
Insulin growth factor-like family member 2 (IGFL2)	OT64M0K7	IGFL2_HUMAN	Increases Expression	[17]
BRCA1-associated RING domain protein 1 (BARD1)	OTTC0Z9Y	BARD1_HUMAN	Decreases Expression	[17]
Fanconi anemia group E protein (FANCE)	OTKRPBW1	FANCE_HUMAN	Decreases Expression	[17]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[22]
Transforming acidic coiled-coil-containing protein 3 (TACC3)	OTRNEZTA	TACC3_HUMAN	Decreases Expression	[17]

References

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• [2] Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. Haematologica. 2015 Mar;100(3):345-56.
• [3] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [4] 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: 7382).
• [5] Autophagy mediates bronchial cell malignant transformation induced by chronic arsenic exposure via MEK/ERK1/2 pathway. Toxicol Lett. 2020 Oct 10;332:155-163. doi: 10.1016/j.toxlet.2020.06.006. Epub 2020 Jul 6.
• [6] Molecular basis of V-ATPase inhibition by bafilomycin A1. Nat Commun. 2021 Mar 19;12(1):1782.
• [7] Nano-sized iron particles may induce multiple pathways of cell death following generation of mistranscripted RNA in human corneal epithelial cells. Toxicol In Vitro. 2017 Aug;42:348-357.
• [8] Autophagy as a compensation mechanism participates in ethanol-induced fetal adrenal dysfunction in female rats. Toxicol Appl Pharmacol. 2018 Apr 15;345:36-47.
• [9] Chronic high glucose inhibits albumin reabsorption by lysosomal alkalinization in cultured porcine proximal tubular epithelial cells (LLC-PK1). Diabetes Res Clin Pract. 2006 Jun;72(3):223-30. doi: 10.1016/j.diabres.2005.10.019. Epub 2005 Nov 28.
• [10] 5-Methoxyflavanone induces cell cycle arrest at the G2/M phase, apoptosis and autophagy in HCT116 human colon cancer cells. Toxicol Appl Pharmacol. 2011 Aug 1;254(3):288-98. doi: 10.1016/j.taap.2011.05.003. Epub 2011 May 15.
• [11] Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca(2+) homeostasis. Chem Biol Interact. 2021 Oct 1;348:109649. doi: 10.1016/j.cbi.2021.109649. Epub 2021 Sep 10.
• [12] Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells. Oncogene. 2016 Aug 25;35(34):4518-28. doi: 10.1038/onc.2015.511. Epub 2016 Feb 8.
• [13] Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells. Toxicol Appl Pharmacol. 2015 Aug 15;287(1):17-25. doi: 10.1016/j.taap.2015.05.001. Epub 2015 May 14.
• [14] LncRNA UCA1 attenuates autophagy-dependent cell death through blocking autophagic flux under arsenic stress. Toxicol Lett. 2018 Mar 1;284:195-204. doi: 10.1016/j.toxlet.2017.12.009. Epub 2017 Dec 15.
• [15] Transcriptomic Landscape of Cisplatin-Resistant Neuroblastoma Cells. Cells. 2019 Mar 12;8(3):235. doi: 10.3390/cells8030235.
• [16] G2019S LRRK2 mutant fibroblasts from Parkinson's disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy. Toxicology. 2014 Oct 3;324:1-9. doi: 10.1016/j.tox.2014.07.001. Epub 2014 Jul 10.
• [17] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [18] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [19] Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate. Clin Pharmacol Ther. 2019 May;105(5):1187-1195.
• [20] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]-Abemaciclib.
• [21] CDK4/6 Inhibition Controls Proliferation of Bladder Cancer and Transcription of RB1. J Urol. 2016 Mar;195(3):771-9. doi: 10.1016/j.juro.2015.08.082. Epub 2015 Aug 28.
• [22] Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2017 Jan 15;124:29-42. doi: 10.1016/j.bcp.2016.10.015. Epub 2016 Nov 2.