Details of the Drug Combination

General Information of Drug Combination (ID: DC5SGO6)

• Drug Combination Name: Cladribine + Venetoclax
• Indication: Acute Myeloid Leukemia; Status: Phase 2 [1]
• Component Drugs:
  Cladribine (DM3JDRP): Small molecular drug
  Venetoclax (DM8I94Y): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cladribine

Disease Entry	ICD 11	Status	REF
Hairy cell leukaemia	2A82.2	Approved	[2]
Multiple sclerosis	8A40	Phase 3	[3]
Relapsing-remitting multiple sclerosis	8A40.0	Phase 3	[4]

Cladribine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine deaminase (ADA)	TTLP57V	ADA_HUMAN	Inhibitor	[6]

Cladribine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[7]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[8]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[8]
Equilibrative nucleoside transporter 3 (SLC29A3)	DTZAWTH	S29A3_HUMAN	Substrate	[9]

Cladribine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Deoxycytidine kinase (DCK)	DE9FGNK	DCK_HUMAN	Metabolism	[10]

Cladribine Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[12]
Lamin-B1 (LMNB1)	OT100T3P	LMNB1_HUMAN	Increases Cleavage	[11]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[13]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[13]
Histone-lysine N-methyltransferase 2A (KMT2A)	OT9GLJI6	KMT2A_HUMAN	Increases Response To Substance	[14]

Indication(s) of Venetoclax

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[5]

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	[15]

Venetoclax Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Expression	[17]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[18]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[18]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Affects Folding	[18]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Binding	[19]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Affects Response To Substance	[20]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Acute Myeloid Leukemia	DCSF8IM	N. A.	Phase 2	[1]

References

• [1] ClinicalTrials.gov (NCT06232655) Cladribine Venetoclax in Monocytic AML
• [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: 4799).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Cladribine: from the bench to the bedside--focus on hairy cell leukemia. Expert Rev Anticancer Ther. 2004 Oct;4(5):745-57.
• [7] Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol Cancer Ther. 2008 Sep;7(9):3092-102.
• [8] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [9] Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J Biol Chem. 2005 Apr 22;280(16):15880-7.
• [10] Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord. 2019 May;30:176-186.
• [11] 2-Chlorodeoxyadenosine alone and in combination with cyclophosphamide and mitoxantrone induce apoptosis in B chronic lymphocytic leukemia cells in vivo. Cancer Detect Prev. 2004;28(6):433-42. doi: 10.1016/j.cdp.2004.08.001.
• [12] Expression and release of chemokines associated with apoptotic cell death in human promonocytic U937 cells and peripheral blood mononuclear cells. Eur J Immunol. 1999 Oct;29(10):3225-35. doi: 10.1002/(SICI)1521-4141(199910)29:10<3225::AID-IMMU3225>3.0.CO;2-0.
• [13] Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr. 2012 Mar;107(6):781-90. doi: 10.1017/S0007114511003631. Epub 2011 Aug 1.
• [14] In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype. Leukemia. 2004 Mar;18(3):521-9. doi: 10.1038/sj.leu.2403253.
• [15] Venclexta FDA label
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.