Drug Details

General Information of the Drug (ID: DR8611)
Name
Bortezomib
Synonyms
[(1S)-3-methyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid; PS 341 (pharmaceutical); MG 341; NSC 681239; NCGC00168751-01; (1S,2R)-Bortezomib; Bortezomib [USAN:INN]; SCHEMBL3676; AC1L3R1E; CHEMBL1530; Bortezomib Impurity (S,S-Isomer); Bortezomib Impurity (R,R-Isomer); Bortezomib Impurity (R,S-Isomer); N-((1S)-1-Benzyl-2-(((1R)-1-(dihydroxyboranyl)-3-methylbutyl)amino)-2-oxoethyl)pyrazinecarboxamide; 1132709-16-0
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Molecular Type
Small molecule
Disease Mantle cell lymphoma [ICD-11: 2A85] Approved [1]
Structure
Click to Download Mol
2D MOL

3D MOL

ADMET Property
Absorption Cmax
The maximum plasma concentration (Cmax) of drug is 57 mcg/L
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability
Clearance
The total body clearance of drug is 102-112 L/h
Half-life
The concentration or amount of drug in body reduced by one-half in 40 - 193 hours
Metabolism
The drug is metabolized via the CYP3A4, CYP2C19, and CYP1A2
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.0836 micromolar/kg/day
Unbound Fraction
The unbound fraction of drug in plasma is 0.17%
Vd
Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 10 L/kg
Water Solubility
The ability of drug to dissolve in water is measured as 3.3 mg/mL
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    Click to Show/Hide the Molecular Information and External Link(s) of This Natural Product
Formula
C19H25BN4O4
PubChem CID
387447
Canonical SMILES
B(C(CC(C)C)NC(=O)C(CC1=CC=CC=C1)NC(=O)C2=NC=CN=C2)(O)O
InChI
1S/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
InChIKey
GXJABQQUPOEUTA-RDJZCZTQSA-N
CAS Number
CAS 179324-69-7
ChEBI ID
CHEBI:52717
GDSC
Bortezomib
TTD Drug ID
D03AJX
DrugBank ID
DB00188
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Arsenic trioxide      Realgar and orpiment     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Expression MAP1LC3A  Molecule Info 
Pathway MAP
Induction Degradation PRAM1  Molecule Info 
Pathway MAP
Induction Degradation SQSTM1  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Increase ROS generation
Increase Unfold protein response
                    In-vitro Model NB4 CVCL_0005 Acute promyelocytic leukemia Homo sapiens
HS-5 CVCL_3720 Healthy Homo sapiens
                    In-vivo Model APL cells (5 * 104 cells/mouse) were injected intravenously via the tail vein into genetically compatible FVB/N recipients, without conditioning with either radiation or chemotherapy.
                    Experimental
                    Result(s)		 A synergistic effect on combining ATO and bortezomib in vitro was noted in both ATO-sensitive and ATO-resistant APL cell lines. The mechanism of this synergy involved downregulation of the nuclear factor-KappaB pathway, increase in unfolded protein response (UPR) and an increase in reactive oxygen species generation in the malignant cell.
          Celastrol      Celastrus strigillosus     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression CXCR4  Molecule Info 
Pathway MAP
Down-regulation Expression MMP-9  Molecule Info 
Pathway MAP
Down-regulation Expression p105  Molecule Info 
Pathway MAP
                    In-vitro Model U266B1 CVCL_0566 Plasma cell myeloma Homo sapiens
NCI-H929 CVCL_1600 Plasma cell myeloma Homo sapiens
KMS-11 CVCL_2989 Plasma cell myeloma Homo sapiens
                    In-vivo Model Male athymic balb/c nude mice were implanted with 2 * 106 cells with Human MM U266 cell lines subcutaneously.
                    Experimental
                    Result(s)		 Celastrol attenuates the invasion and migration and augments the anticancer effects of bortezomib in a xenograft mouse model of multiple myeloma.
          Curcumin      Hellenia speciosa     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Phosphorylation JNK1  Molecule Info 
Pathway MAP
Down-regulation Expression RELA  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Up-regulation Increase NFKBIA stabilization
                    In-vitro Model NCI-H929 CVCL_1600 Plasma cell myeloma Homo sapiens
                    Experimental
                    Result(s)		 Curcumin enhance the cytotoxicity of PS-341 by interacting with NF-kappaB, at least in part, through JNK mechanism.
          Daunorubicin      Streptomyces peucetius     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP8  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP9  Molecule Info 
Pathway MAP
                    In-vitro Model Jurkat CVCL_0065 T acute lymphoblastic leukemia Homo sapiens
MOLT-4 CVCL_0013 Adult T acute lymphoblastic leukemia Homo sapiens
Daudi CVCL_0008 EBV-related Burkitt lymphoma Homo sapiens
                    Experimental
                    Result(s)		 The combination of bortezomib and daunorubicin significantly enhanced their apoptosis inducing effect in T ALL cells, which may warrant further investigation in preclinical and clinical investigations.
          Epigallocatechin gallate      Hamamelis virginiana     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP8  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP9  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation NFKBIA  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
Down-regulation Expression and phosphorylation RELA  Molecule Info 
Pathway MAP
                    In-vitro Model KM-3 CVCL_0011 Multiple myeloma Homo sapiens
                    Experimental
                    Result(s)		 Combined EGCG and bortezomib showed synergistic anticancer effect partly via regulating NF-kappaB pathway.
          Flavopiridol      Dysoxylum binectariferum     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-xL  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation BRD4  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation CRKL  Molecule Info 
Pathway MAP
Up-regulation Expression DIABLO  Molecule Info 
Pathway MAP
Up-regulation Phosphorylation ERK2  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation HCK  Molecule Info 
Pathway MAP
Up-regulation Phosphorylation JNK1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation JTK8  Molecule Info 
Pathway MAP
Up-regulation Phosphorylation NFKBIA  Molecule Info 
Pathway MAP
Down-regulation Expression p105  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT3  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT5B  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction Loss of mitochondrial membrane potential
Up-regulation Cytochrome c release
                    In-vitro Model K-562 CVCL_0004 Chronic myelogenous leukemia Homo sapiens
LAMA-84 CVCL_0388 Chronic myelogenous leukemia Homo sapiens
U-937 CVCL_0007 Adult acute monocytic leukemia Homo sapiens
HL-60 CVCL_0002 Adult acute myeloid leukemia Homo sapiens
Raji CVCL_0511 EBV-related Burkitt lymphoma Homo sapiens
Jurkat CVCL_0065 T acute lymphoblastic leukemia Homo sapiens
CCRF-CEM CVCL_0207 T acute lymphoblastic leukemia Homo sapiens
                    Experimental
                    Result(s)		 Bortezomib interacts synergistically with flavopiridol to induce mitochondrial dysfunction and apoptosis, blockade of the IkappaB/NF-kappaB pathway and activation of the SAPK/JNK cascade.
          Thymoquinone      Nigella sativa     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Expression CASP3  Molecule Info 
Pathway MAP
Up-regulation Expression COL11A2  Molecule Info 
Pathway MAP
Down-regulation Expression IL6  Molecule Info 
Pathway MAP
Down-regulation Expression MKI67  Molecule Info 
Pathway MAP
Down-regulation Expression p105  Molecule Info 
Pathway MAP
Down-regulation Expression RELA  Molecule Info 
Pathway MAP
Down-regulation Expression TNF  Molecule Info 
Pathway MAP
Down-regulation Expression VEGFA  Molecule Info 
Pathway MAP
                    In-vitro Model U266B1 CVCL_0566 Plasma cell myeloma Homo sapiens
NCI-H929 CVCL_1600 Plasma cell myeloma Homo sapiens
KMS-11 CVCL_2989 Plasma cell myeloma Homo sapiens
RPMI-8226 CVCL_0014 Plasma cell myeloma Homo sapiens
                    In-vivo Model Five-week-old athymic nu/nu male Balb/c mice were implanted subcutaneously in the right flank with U266 cells (2 * 106 cells/100 uL of PBS/Matrigel).
                    Experimental
                    Result(s)		 Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-KappaB regulated gene products in multiple myeloma xenograft mouse model.
Target and Pathway
Target(s) Core proteasome 20S complex (PS 20S)  Molecule Info  [9]
Nuclear factor NF-kappa-B (NFKB)  Molecule Info  [10]
KEGG Pathway MAPK signaling pathway Click to Show/Hide
2 NF-kappa B signaling pathway
3 Osteoclast differentiation
4 Legionellosis
5 HTLV-I infection
6 Epstein-Barr virus infection
7 Pathways in cancer
8 Viral carcinogenesis
NetPath Pathway IL5 Signaling Pathway Click to Show/Hide
Panther Pathway Apoptosis signaling pathway Click to Show/Hide
2 B cell activation
3 Inflammation mediated by chemokine and cytokine signaling pathway
4 T cell activation
5 Toll receptor signaling pathway
Pathwhiz Pathway Intracellular Signalling Through Adenosine Receptor A2a and Adenosine Click to Show/Hide
2 Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
Pathway Interaction Database IL12-mediated signaling events Click to Show/Hide
2 Alternative NF-kappaB pathway
Reactome RIP-mediated NFkB activation via ZBP1 Click to Show/Hide
2 DEx/H-box helicases activate type I IFN and inflammatory cytokines production
3 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
4 Interleukin-1 processing
5 IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)
6 IkBA variant leads to EDA-ID
7 Dectin-1 mediated noncanonical NF-kB signaling
8 NIK-->noncanonical NF-kB signaling
9 TRAF6 mediated NF-kB activation
WikiPathways Toll-like receptor signaling pathway Click to Show/Hide
2 DNA Damage Response (only ATM dependent)
3 SIDS Susceptibility Pathways
4 Nuclear Receptors Meta-Pathway
5 Cytosolic sensors of pathogen-associated DNA
6 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
7 EBV LMP1 signaling
8 TNF alpha Signaling Pathway
9 TSLP Signaling Pathway
10 Neural Crest Differentiation
11 TWEAK Signaling Pathway
12 RANKL/RANK Signaling Pathway
13 RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways
14 Interleukin-1 processing
15 Folate Metabolism
16 Vitamin B12 Metabolism
17 Selenium Micronutrient Network
18 Regulation of toll-like receptor signaling pathway
References
Reference 1 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Reference 2 Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia. Leukemia. 2016 Nov;30(11):2169-2178.
Reference 3 Celastrol Attenuates the Invasion and Migration and Augments the Anticancer Effects of Bortezomib in a Xenograft Mouse Model of Multiple Myeloma. Front Pharmacol. 2018 May 3;9:365.
Reference 4 Curcumin enhances cytotoxic effects of bortezomib in human multiple myeloma H929 cells: potential roles of NF-kappaB/JNK. Int J Mol Sci. 2012;13(4):4831-8.
Reference 5 Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia. Mol Med Rep. 2017 Jul;16(1):101-108.
Reference 6 Potentiation of (-)-epigallocatechin-3-gallate-induced apoptosis by bortezomib in multiple myeloma cells. Acta Biochim Biophys Sin (Shanghai). 2009 Dec;41(12):1018-26.
Reference 7 Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood. 2004 Jul 15;104(2):509-18.
Reference 8 Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-KappaB regulated gene products in multiple myeloma xenograft mouse model. Oncotarget. 2014 Feb 15;5(3):634-48.
Reference 9 Selected novel anticancer treatments targeting cell signaling proteins. Oncologist. 2001;6(6):517-37.
Reference 10 Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood. 2002 Jun 1;99(11):4079-86.
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