Details of the Drug Combination

General Information of Drug Combination (ID: DCXVNC5)

• Drug Combination Name: Idelalisib + Acalabrutinib
• Indication: Diffuse large B cell lymphoma; Status: Investigative [1]
• Component Drugs:
  Idelalisib (DM602WT): Small molecular drug
  Acalabrutinib (DM7GCVW): N.A.
• High-throughput Screening Result:
  Testing Cell Line: TMD8
  Zero Interaction Potency (ZIP) Score: 4.15
  Bliss Independence Score: 4.07
  Loewe Additivity Score: 4.2
  LHighest Single Agent (HSA) Score: 7.94

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Idelalisib

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[2]
Small lymphocytic lymphoma	2A82.0	Approved	[3]
Follicular lymphoma	2A80	Investigative	[3]

Idelalisib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase delta (PIK3CD)	TTGBPJE	PK3CD_HUMAN	Inhibitor	[8]

Idelalisib Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]

Idelalisib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Idelalisib Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Response To Substance	[11]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[12]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Affects Response To Substance	[11]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[13]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[12]
Phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1)	OTWE5G4T	P3IP1_HUMAN	Increases Expression	[13]
RNA cytidine acetyltransferase (NAT10)	OT6JQO26	NAT10_HUMAN	Increases Expression	[14]

Indication(s) of Acalabrutinib

Disease Entry	ICD 11	Status	REF
leukaemia	2A60-2B33	Approved	[4]
Mantle cell lymphoma	2A85.5	Approved	[5]
Chronic lymphocytic leukaemia	2A82.0	Phase 3	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]

Acalabrutinib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase BTK (ATK)	TTGM6VW	BTK_HUMAN	Inhibitor	[5]
HUMAN bruton tyrosine kinase (BTK)	TTOWPER	BTK_HUMAN	Inhibitor	[15]

Acalabrutinib Interacts with 2 DME Molecule(s)

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

Acalabrutinib Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Affects Expression	[17]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[17]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Metabolism	[18]

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: 6741).
• [3] Idelalisib FDA Label
• [4] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 210259
• [5] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] ClinicalTrials.gov (NCT04346199) Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19.. U.S. National Institutes of Health.
• [8] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [9] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB09054)
• [10] FDA label of Idelalisib. The 2020 official website of the U.S. Food and Drug Administration.
• [11] PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. Toxicol Appl Pharmacol. 2019 Oct 15;381:114729. doi: 10.1016/j.taap.2019.114729. Epub 2019 Aug 22.
• [12] Roles of pulmonary telocytes in airway epithelia to benefit experimental acute lung injury through production of telocyte-driven mediators and exosomes. Cell Biol Toxicol. 2023 Apr;39(2):451-465. doi: 10.1007/s10565-021-09670-5. Epub 2022 Jan 3.
• [13] Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3K inhibition through PIK3IP1. Cell Cycle. 2013 Jun 15;12(12):1892-900. doi: 10.4161/cc.24928. Epub 2013 May 15.
• [14] Regulatory roles of NAT10 in airway epithelial cell function and metabolism in pathological conditions. Cell Biol Toxicol. 2023 Aug;39(4):1237-1256. doi: 10.1007/s10565-022-09743-z. Epub 2022 Jul 25.
• [15] AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19
• [16] FDA label of Acalabrutinib. The 2020 official website of the U.S. Food and Drug Administration.
• [17] Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol. 2020 Jun 5;5(48):eabd0110. doi: 10.1126/sciimmunol.abd0110. Epub 2020 Jun 5.
• [18] Functional assessment of the effects of CYP3A4 variants on acalabrutinib metabolism in vitro. Chem Biol Interact. 2021 Aug 25;345:109559. doi: 10.1016/j.cbi.2021.109559. Epub 2021 Jun 18.