Details of the Drug Combination

General Information of Drug Combination (ID: DCTO5NB)

• Drug Combination Name: Acalabrutinib + Thiotepa
• Indication: Refractory and Relapsed Primary CNS Lymphoma; Status: Phase 1 [1]
• Component Drugs:
  Acalabrutinib (DM7GCVW): N.A.
  Thiotepa (DMIZKOP): 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	[8]

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	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]

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	[10]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Metabolism	[11]

Indication(s) of Thiotepa

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[6]
Immunodeficiency	4A00-4A85	Approved	[7]
Leukemia	N.A.	Approved	[7]
Urinary bladder cancer	N.A.	Approved	[7]
Classic Hodgkin lymphoma	N.A.	Investigative	[7]
Neuroblastoma	2D11.2	Investigative	[7]

Thiotepa Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[14]

Thiotepa Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Export	[15]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Affects Export	[15]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[12]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[12]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[12]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[12]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[12]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[17]
Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1)	OTAYZZE6	AL3A1_HUMAN	Affects Response To Substance	[18]
Aldehyde dehydrogenase 1A1 (ALDH1A1)	OTCUWZKB	AL1A1_HUMAN	Affects Response To Substance	[18]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Response To Substance	[19]
N-glycosylase/DNA lyase (OGG1)	OTJ97TF3	OGG1_HUMAN	Decreases Response To Substance	[20]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Response To Substance	[14]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Affects Response To Substance	[21]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Export	[15]

References

• [1] ClinicalTrials.gov (NCT05021770) Orelabrutinib in Combination With Thiotepa in Refractory and Relapsed Primary CNS 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] 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: 7622).
• [7] Thiotepa FDA Label
• [8] AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19
• [9] FDA label of Acalabrutinib. The 2020 official website of the U.S. Food and Drug Administration.
• [10] 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.
• [11] 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.
• [12] Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-xL protein levels. Cell Death Differ. 2000 Jun;7(6):574-86. doi: 10.1038/sj.cdd.4400688.
• [13] Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA. Cancer Chemother Pharmacol. 2002 Jun;49(6):461-7.
• [14] Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys. 1999 Jun 1;366(1):89-94.
• [15] Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa. Br J Clin Pharmacol. 2009 Jan;67(1):50-60. doi: 10.1111/j.1365-2125.2008.03321.x. Epub 2008 Nov 17.
• [16] The naturally occurring cytochrome P450 (P450) 2B6 K262R mutant of P450 2B6 exhibits alterations in substrate metabolism and inactivation. Drug Metab Dispos. 2005 Jun;33(6):795-802.
• [17] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [18] Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin. Pharmacogenet Genomics. 2008 Nov;18(11):1009-15. doi: 10.1097/FPC.0b013e328313aaa4.
• [19] [Establishment of MRP-overexpression subline of bladder carcinoma and its MDR phenotype]. Zhonghua Zhong Liu Za Zhi. 2000 Jul;22(4):273-5.
• [20] Protection of mammalian cells against chemotherapeutic agents thiotepa, 1,3-N,N'-bis(2-chloroethyl)-N-nitrosourea, and mafosfamide using the DNA base excision repair genes Fpg and alpha-hOgg1: implications for protective gene therapy applications. J Pharmacol Exp Ther. 2001 Mar;296(3):825-31.
• [21] Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999 Apr 1;18(13):2241-51. doi: 10.1038/sj.onc.1202526.