Details of the Drug Combination

General Information of Drug Combination (ID: DC7Y05T)

• Drug Combination Name: Talazoparib + Selinexor
• Indication: Advanced Refractory Solid Tumors; Status: Phase 1 [1]
• Component Drugs:
  Talazoparib (DM1KS78): Small molecular drug
  Selinexor (DMBD4K3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Talazoparib

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Psoriatic arthritis	FA21	Phase 3	[3]

Talazoparib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Poly [ADP-ribose] polymerase (PARP)	TTEBCY8	NOUNIPROTAC	Inhibitor	[2]

Talazoparib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]

Talazoparib Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Affects Expression	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Affects Expression	[10]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Affects Expression	[10]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Affects Expression	[10]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Expression	[10]
Poly polymerase 2 (PARP2)	OTYL81ZI	PARP2_HUMAN	Decreases Activity	[11]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Response To Substance	[10]
Fumarate hydratase, mitochondrial (FH)	OTEQWU6Q	FUMH_HUMAN	Increases Response To Substance	[12]
Succinate dehydrogenase iron-sulfur subunit, mitochondrial (SDHB)	OTRE1M1T	SDHB_HUMAN	Increases Response To Substance	[12]

Indication(s) of Selinexor

Disease Entry	ICD 11	Status	REF
Multiple myeloma	2A83	Approved	[4]
Liposarcoma	2B59	Phase 3	[5]
Neuroendocrine cancer	2B72.1	Phase 3	[5]
Acute myeloid leukaemia	2A60	Phase 2	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[7]
Diffuse large B-cell lymphoma	2A81	Phase 2	[6]
Recurrent glioblastoma	2A00.00	Phase 2	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]

Selinexor Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Exportin-1 (XPO1)	TTCJUR4	XPO1_HUMAN	Inhibitor	[13]

Selinexor Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[14]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[14]

Selinexor Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor protein p73 (TP73)	OT0LUO47	P73_HUMAN	Increases Expression	[15]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[15]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[15]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[15]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Increases Expression	[15]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[15]

References

• [1] ClinicalTrials.gov (NCT05035745) Selinexor & Talazoparib in Advanced Refractory Solid Tumors; Advanced/Metastatic Triple Negative Breast Cancer (START)
• [2] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [3] 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: 8313).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] ClinicalTrials.gov (NCT04349098) Evaluation of Activity and Safety of Oral Selinexor in Participants With Severe COVID-19 Infection. U.S. National Institutes of Health.
• [8] ClinicalTrials.gov (NCT02025985) Phase II Study of KPT-330 (Selinexor) in Female Patients With Advanced Gynaecologic Malignancies. U.S. National Institutes of Health.
• [9] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB11760)
• [10] BMN 673 (talazoparib): A potent PARP inhibitor for triple negative breast cancer with different genetic profile. J Biochem Mol Toxicol. 2019 May;33(5):e22286. doi: 10.1002/jbt.22286. Epub 2019 Jan 23.
• [11] Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. J Med Chem. 2017 Feb 23;60(4):1262-1271. doi: 10.1021/acs.jmedchem.6b00990. Epub 2016 Dec 21.
• [12] Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet. 2018 Aug;50(8):1086-1092. doi: 10.1038/s41588-018-0170-4. Epub 2018 Jul 16.
• [13] Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents. Semin Cancer Biol. 2014 August; 0: 62-73.
• [14] FDA label of Selinexor. The 2020 official website of the U.S. Food and Drug Administration.
• [15] The synergy of the XPO1 inhibitors combined with the BET inhibitor INCB057643 in high-grade B-cell lymphoma via downregulation of MYC expression. Sci Rep. 2023 Oct 29;13(1):18554. doi: 10.1038/s41598-023-45721-z.