Details of the Drug Combination

General Information of Drug Combination (ID: DCMHUZ1)

• Drug Combination Name: Acalabrutinib + Venetoclax
• Indication: Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma; Status: Phase 3 [1]
• Component Drugs:
  Acalabrutinib (DM7GCVW): N.A.
  Venetoclax (DM8I94Y): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Acalabrutinib

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

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	[3]
HUMAN bruton tyrosine kinase (BTK)	TTOWPER	BTK_HUMAN	Inhibitor	[7]

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	[8]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[8]

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	[9]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[9]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Metabolism	[10]

Indication(s) of Venetoclax

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[6]

Venetoclax Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]

Venetoclax Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[12]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Activity	[13]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[12]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Folding	[15]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[14]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[15]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Affects Folding	[15]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Binding	[16]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Affects Response To Substance	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Chronic Lymphocytic Leukemia	DC04QN3	N. A.	Phase 3	[18]

References

• [1] ClinicalTrials.gov (NCT05057494) A Study of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
• [2] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 210259
• [3] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19
• [8] FDA label of Acalabrutinib. The 2020 official website of the U.S. Food and Drug Administration.
• [9] 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.
• [10] 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.
• [11] Venclexta FDA label
• [12] ZCL-082, a boron-containing compound, induces apoptosis of non-Hodgkin's lymphoma via targeting p90 ribosomal S6 kinase 1/NF-B signaling pathway. Chem Biol Interact. 2022 Jan 5;351:109770. doi: 10.1016/j.cbi.2021.109770. Epub 2021 Nov 30.
• [13] Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet. 2015 Sep;47(9):1020-1029. doi: 10.1038/ng.3362. Epub 2015 Jul 27.
• [14] HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. Curr Issues Mol Biol. 2023 Aug 23;45(9):7011-7026. doi: 10.3390/cimb45090443.
• [15] Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019 Jan 15;9(2):4. doi: 10.1038/s41408-018-0165-5.
• [16] Prospective Drug Candidates as Human Multidrug Transporter ABCG2 Inhibitors: an In Silico Drug Discovery Study. Cell Biochem Biophys. 2021 Jun;79(2):189-200. doi: 10.1007/s12013-021-00985-y. Epub 2021 May 5.
• [17] Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors. Cancer Res Commun. 2023 Dec 8;3(12):2497-2509. doi: 10.1158/2767-9764.CRC-23-0350.
• [18] ClinicalTrials.gov (NCT03836261) Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL