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
No information available.
Summary of Clinical Use Click here for help
May be used to treat multiple myeloma in patients unsuccessfully treated with at least two previous therapies. Bortezomib is delivered by injection. The marketed drug Velcade, contains bortezomib as the mannitol boronic ester.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome. Inhibitors of proteasome activity are antiproliferative and pro-apoptotic in nature. Proteasome inhibition leads to an increase in intracellular pro-apoptotic proteins, which promote cell-cycle arrest and cell-death [2].
Pharmacokinetics Click here for help
Biotransformation/Metabolism
Bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2D6, 2C19, 2C9, and 1A2. Deboronated metabolites are inactive as 26S proteasome inhibitors.
Elimination
The pathways of elimination of bortezomib have not been characterized in humans.
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