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 compound also has antimalarial activity. 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
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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
1. Alexander T, Sarfert R, Klotsche J, Kühl AA, Rubbert-Roth A, Lorenz HM, Rech J, Hoyer BF, Cheng Q, Waka A et al.. (2015)
The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus.
Ann Rheum Dis, 74 (7): 1474-8. [PMID:25710470]
2. Bonvini P, Zorzi E, Basso G, Rosolen A. (2007)
Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma.
Leukemia, 21 (4): 838-42. [PMID:17268529]
3. Ciechanover A. (2005)
Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture).
Angew Chem Int Ed Engl, 44 (37): 5944-67. [PMID:16142822]
4. Groll M, Berkers CR, Ploegh HL, Ovaa H. (2006)
Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome.
Structure, 14 (3): 451-6. [PMID:16531229]
5. Jakez-Ocampo J, Atisha-Fregoso Y, Llorente L. (2015)
Refractory primary Sjögren syndrome successfully treated with bortezomib.
J Clin Rheumatol, 21 (1): 31-2. [PMID:25539431]
6. Mazepa MA, Raval JS, Moll S, Ma A, Park YA. (2014)
Bortezomib induces clinical remission and reduction of ADAMTS13 inhibitory antibodies in relapsed refractory idiopathic thrombotic thrombocytopenic purpura.
Br J Haematol, 164 (6): 900-2. [PMID:24345005]
7. Nakamura H, Watanabe M, Ban HS, Nabeyama W, Asai A. (2009)
Synthesis and biological evaluation of boron peptide analogues of Belactosin C as proteasome inhibitors.
Bioorg Med Chem Lett, 19 (12): 3220-4. [PMID:19428245]
8. Reynolds JM, El Bissati K, Brandenburg J, Günzl A, Mamoun CB. (2007)
Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B.
BMC Clin Pharmacol, 7: 13. [PMID:17956613]
9. Wang Y, Zhou W, Zhang Z. (2015)
Successful treatment of warm-type haemolytic anaemia with bortezomib in a rituximab-failed systemic lupus erythematosus patient.
Rheumatology (Oxford), 54 (1): 194-5. [PMID:25288787]
10. Xie SC, Gillett DL, Spillman NJ, Tsu C, Luth MR, Ottilie S, Duffy S, Gould AE, Hales P, Seager BA et al.. (2018)
Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome.
J Med Chem, 61 (22): 10053-10066. [PMID:30373366]
11. Zhang H, Liu Z, Huang L, Hou J, Zhou M, Huang X, Hu W, Liu Z. (2017)
The short-term efficacy of bortezomib combined with glucocorticoids for the treatment of refractory lupus nephritis.
Lupus, 26 (9): 952-958. [PMID:28059023]