Bortezomib

CovInDB Drug

DB00188

Name

Bortezomib

Molecular Formula

C₁₉H₂₅BN₄O₄

Molecular Weight

384.2 g/mol

Description

Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. The boron atom within bortezomib catalytically binds the active site of the 26S proteasome with high affinity and specificity, thereby resulting in cell cycle arrest and apoptosis. In normal cells, the proteasome is involved in degradation of ubiquitylated proteins that have been tagged for destruction because they are damaged or unneeded by the cell. However, in cancerous cells, proteasome activity degrades pro-apoptotic proteins such as p53 that would normally result in programmed cell death of the dysfunctional cells. Proteasome inhibitors such as bortezomib interrupt this process, resulting in destruction of cancerous cells. Bortezomib is currently approved in the United States for the treatment of relapsed multiple myeloma and mantle cell lymphoma.

Status

approved, investigational

Structure

  Warhead   Similar Compounds

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SDF 2D SDF 3D

Indication

For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.

Mechanism of action

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Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The active site of the proteasome has chymotrypsin-like, trypsin-like, and postglutamyl peptide hydrolysis activity. The 26S proteasome degrades various proteins critical to cancer cell survival, such as cyclins, tumor suppressors, BCL-2, and cyclin-dependent kinase inhibitors. Inhibition of these degradations sensitizes cells to apoptosis. Bortezomib is a potent inhibitor of 26S proteasome, which sensitizes activity in dividing multiple myeloma and leukemic cells, thus inducing apoptosis. In addition, bortezomib appears to increase the sensitivity of cancer cells to traditional anticancer agents (e.g., gemcitabine, cisplatin, paclitaxel, irinotecan, and radiation).

IUPAC Name

[(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid

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

Canonical SMILES

CC(C)C[C@H](NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)C1=CN=CC=N1)B(O)O

Reference

DrugBank

Warhead

Boronic Acid

Target

Proteasome subunit beta type-5   [ UniProt: P28074 ]

Proteasome subunit beta type-1   [ UniProt: P20618 ]

Site

THR-1

Inhibition Mechanism

Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome

logP

0.89

Computed by ALOGPS

logS

-3.86

Computed by ALOGPS

Heavy Atom Count

28

Computed by RDKit

Ring Count

2

Computed by RDKit

Hydrogen Bond Acceptor Count

6

Computed by RDKit

Hydrogen Bond Donor Count

4

Computed by RDKit

Rotatable Bond Count

9

Computed by RDKit

Topological Polar Surface Area

124.44 Ų

Computed by RDKit

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