Details of the Drug Combination

General Information of Drug Combination (ID: DCFWL4S)

• Drug Combination Name: Venetoclax + Trabectedin
• Indication: Refractory Chronic Lymphocytic Leukemia; Status: Phase 1 [1]
• Component Drugs:
  Venetoclax (DM8I94Y): Small molecular drug
  Trabectedin (DMG3Y89): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Venetoclax

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

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	[6]

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	[7]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Activity	[8]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Expression	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[7]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Folding	[10]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[10]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[9]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[10]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Affects Folding	[10]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Binding	[11]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Affects Response To Substance	[12]

Indication(s) of Trabectedin

Disease Entry	ICD 11	Status	REF
Leiomyosarcoma	2B58	Approved	[3]
Liposarcoma	2B59	Approved	[3]
Solid tumour/cancer	2A00-2F9Z	Approved	[4]
Ovarian cancer	2C73	Phase 3	[5]

Trabectedin Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[14]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[15]

Trabectedin Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[16]
Transferrin receptor protein 1 (TFRC)	OT8ZPBDL	TFR1_HUMAN	Increases Expression	[17]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[16]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[16]
Cytoplasmic aconitate hydratase (ACO1)	OT2VUR7L	ACOHC_HUMAN	Increases Expression	[17]
Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4)	OTRAFFX2	GPX4_HUMAN	Decreases Expression	[17]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Increases Expression	[16]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Increases Expression	[17]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Expression	[17]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[17]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Response To Substance	[18]

References

• [1] ClinicalTrials.gov (NCT03884972) Trabectedin and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Resistant or Intolerant to a BTK Inhibitor
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Trabectedin FDA Label
• [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: 2774).
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Venclexta FDA label
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] ZNF93 increases resistance to ET-743 (Trabectedin; Yondelis) and PM00104 (Zalypsis) in human cancer cell lines. PLoS One. 2009 Sep 9;4(9):e6967. doi: 10.1371/journal.pone.0006967.
• [14] In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anti-cancer drug. Invest New Drugs. 2006 Jan;24(1):3-14.
• [15] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [16] Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters. Mol Pharmacol. 2005 Nov;68(5):1496-503. doi: 10.1124/mol.105.013615. Epub 2005 Jun 16.
• [17] Trabectedin induces ferroptosis via regulation of HIF-1/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells. Chem Biol Interact. 2023 Jan 5;369:110262. doi: 10.1016/j.cbi.2022.110262. Epub 2022 Nov 14.
• [18] The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary. Clin Cancer Res. 2011 Jul 1;17(13):4462-73. doi: 10.1158/1078-0432.CCR-10-2987. Epub 2011 May 27.