bortezomib   Click here for help

GtoPdb Ligand ID: 6391

Synonyms: peptide boronate | PS-341 | Velcade®
Approved drug PDB Ligand Immunopharmacology Ligand Antimalarial Ligand
bortezomib is an approved drug (FDA (2003), EMA (2004))
Compound class: Synthetic organic
Comment: Bortezomib is a dipeptide (Phe-Leu), with a pyrazinoic acid protecting the N-terminus and a boronic acid replacing the C-terminal carboxylic acid. The boron atom is believed to interact with and inactivate the catalytic site on β subunits which form the active core of the proteasome, preferentially binding β5 active site [4]. Bortezomib is the first-in-class proteasome inhibitor to be approved for clinical use.
Proteasome activity is reviewed in [3].

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 4
Rotatable bonds 11
Topological polar surface area 124.44
Molecular weight 384.2
XLogP 1.01
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES CC(CC(B(O)O)NC(=O)C(NC(=O)c1cnccn1)Cc1ccccc1)C
Isomeric SMILES CC(C[C@@H](B(O)O)NC(=O)[C@@H](NC(=O)c1cnccn1)Cc1ccccc1)C
InChI 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
InChI Key GXJABQQUPOEUTA-RDJZCZTQSA-N
Bioactivity Comments
Bortezomib has been shown to inhibit the chymotrypsin-like (aka β5) activity of the human 26S proteasome [7].
The interaction table below provides data from an evaluation of the antimalarial (asexual blood stage) activity of bortezomib, using a panel of P. falciparum strains. The compound shows no evidence of reduced potency against drug resistant strains [8].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
proteasome 20S subunit beta 5 Primary target of this compound Hs Inhibitor Inhibition 7.7 pIC50 - 7
pIC50 7.7 (IC50 2x10-8 M) [7]
Selectivity at other protein targets
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum proteasome subunit beta type-5 Pf Inhibitor Inhibition 7.3 pIC50 - 10
pIC50 7.3 (IC50 5.3x10-8 M) Fluorogenic peptide assay used to assess purified Pf20S proteasome activity [10]
Whole organism assay data
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MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference
Plasmodium falciparum proteasome subunit beta type-5 Pf3D7 Parasite growth inhibition assay - - 7.5 pIC50 - 8
pIC50 7.5 (IC50 3.1x10-8 M) [3H]-hypoxanthine incorporation [8]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum proteasome subunit beta type-5 PfHB3 Parasite growth inhibition assay - - 7.5 pIC50 - 8
pIC50 7.5 (IC50 3.1x10-8 M) [3H]-hypoxanthine incorporation [8]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum proteasome subunit beta type-5 PfDd2 Parasite growth inhibition assay - - 7.4 pIC50 - 8
pIC50 7.4 (IC50 3.7x10-8 M) [3H]-hypoxanthine incorporation [8]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Plasmodium falciparum proteasome subunit beta type-5 PfW2 Parasite growth inhibition assay - - 7.4 pIC50 - 8
pIC50 7.4 (IC50 4.3x10-8 M) [3H]-hypoxanthine incorporation [8]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
Ligand mentioned in the following text fields