A2614-25mg | Bortezomib (PS-341) [179324-69-7] Quimigen Portugal

Background

Bortezomib (originally codenamed PS-341) is the first therapeutic proteasome inhibitor to the tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. [1] The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid. Peptides are written N-terminus to C-terminus, and this convention is used here even though the "C-terminus" is a boronic acid instead of a carboxylic acid. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome. [2] Some intracellular peptides have been shown to be biologically active, and so the effect of bortezomib on the levels of intracellular peptides may contribute to the biological and/or side effects of the drug.

A potent (Ki = 0.6 nM), specific and reversible proteasome inhibitor. It inhibits cell proliferation of H460 cells (Human non-small cell lung cancer cell lines) with an IC₅₀ of 0.1 µM.

References:
1. Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
2. Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". In Gartel, Andrei L. PLoS One 8 (8): e53263.

Product Citation

1. Mikhail S. Chesnokov, Marianna Halasi, et al. "Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells." Cell Death Dis. 2021 Jul 14;12(7):704. PMID:34262016
2. Qi Zhu, Xu-xu Zhuang, et al. "Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models." Phytomedicine. 2021 Jul;87:153578. PMID:34038839
3. David Romero-Suarez, Tune Wulff, et al. "A Reporter System for Cytosolic Protein Aggregates in Yeast." ACS Synth Biol. 2021 Mar 19;10(3):466-477. PMID:33577304
4. Yue Peng, Xiaofeng Sun, et al. "Role of DNA methylation on human CTSG in dermatomyositic myoideum." Cell Biol Int. 2020 Dec;44(12):2409-2415. PMID:32813288
5. Dana Mamriev, Ruqaia Abbas, et al. "A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2." Cell Death Dis. 2020 Jun 25;11(6):483. PMID:32587235
6. Haiyang Yu, Shan Lu, et al. "TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli." bioRxiv. March 29, 2020.
7. Tsai YJ, Hao CY, et al. "Expression of long pentraxin 3 in human nasal mucosa fibroblasts, tissues, and secretions of chronic rhinosinusitis without nasal polyps." J Mol Med (Berl). 2020;98(5):673-689. PMID:32239253
8. Lin J, Boon L, et al. "Desensitization using imlifidase and EndoS enables chimerism induction in allosensitized recipient mice." Am J Transplant. 2020;10.1111/ajt.15851. PMID:32185855
9. Tracy Cai X, Li H, et al. "AWD regulates timed activation of BMP signaling in intestinal stem cells to maintain tissue homeostasis." Nat Commun. 2019 Jul 5;10(1):2988. PMID:31278345
10. Timms RT, Zhang Z, et al. "A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation." Science. 2019 Jul 5;365(6448). pii: eaaw4912. PMID:31273098
11. SemraUnalad, SemaArslanc, et al. "Design and characterization of polycaprolactone-gelatin-graphene oxide scaffolds for drug influence on glioblastoma cells." European Polymer Journal. Volume 115, June 2019, Pages 157-165.
12. Rodriguez-Fernandez IA, Qi Y, et al. "Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction." Nat Commun. 2019 Mar 5;10(1):1050. PMID:30837466
13. Yuan NN, Cai CZ, et al. "Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology." Front Pharmacol. 2019 Jan 28;10:16.nbsp;PMID:30745870
14. Cui-ZanCai, He-FengZhou, et al. "Natural alkaloid harmine promotes degradation of Alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation." Phytomedicine. Available online 30 January 2019, 152842.
15. Ayse Tarbin Jannuzzi, Gulce Sari, et al. "Proteasomal Inhibition with Bortezomib Causes Selective Autophagy Upregulation and Perinuclear Clustering of Mitochondria in Human Neuronal Cells†." Proceedings 2018, 2(25), 1583.
16. Gibbs DJ, Tedds HM, et al. "Oxygen-dependent proteolysis regulates the stability of angiosperm polycomb repressive complex 2 subunit VERNALIZATION 2." Nat Commun. 2018 Dec 21;9(1):5438. PMID:30575749
17. Oladimeji PO, Wright WC, et al. "RNA interference screen identifies NAA10 as a regulator of PXR transcription." Biochem Pharmacol. 2018 Dec 16;160:92-109. PMID:30566892
18. Karademir B, Sari G, et al. "Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib." Sci Rep.2018 Nov 5;8(1):16318. PMID:30397214
19. Xiang Y, Wang M, et al. "Mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct isoforms within the coupled positive and negative feedback circuits." Toxicol Appl Pharmacol. 2018 Dec 1;360:212-235. PMID:30287392
20. Rozic G, Paukov L, et al. "STK405759 as a combination therapy with bortezomib or dexamethasone, in in vitro and in vivo multiple myeloma models." Oncotarget. 2018 Jul 31;9(59):31367-31379. PMID:30140376
21. Xinchun Li, Li Zhong, et al. "Phosphorylation of IRS4 by CK1γ2 promotes its degradation by CHIP through the ubiquitin/lysosome pathway." Theranostics, 2018, Vol. 8, Issue13.
22. Yuancai Xiang, Josefin Halin, et al."Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor." bioRxiv.2018. March 27.
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24. Yuancai Xiang, et al."Molecular mechanisms controlling the multistage post-translational processing of endogenous Nrf1/TCF11 proteins to yield distinct proteoforms within the coupled positive and negative feedback circuits."bioRxiv.2018. April 12.
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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	384.24
Cas No.	179324-69-7
Formula	C₁₉H₂₅BN₄O₄
Synonyms	Bortezomib,PS-341,LDP-341,MLM341,MG-341,NSC-681239
Solubility	insoluble in EtOH; insoluble in H2O; ≥19.21 mg/mL in DMSO
Chemical Name	[(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid
SDF	Download SDF
Canonical SMILES	B(C(CC(C)C)NC(=O)C(CC1=CC=CC=C1)NC(=O)C2=NC=CN=C2)(O)O
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	Canine malignant melanoma cell lines (CMM-1, CMM-2, ChMC, KMeC, LMeC, OMJ, OMS, OMK, and NML
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	72h; IC50=3.5~5.6 nM (nine kinds of cells)
Applications	Bortezomib potently suppressed the growth in 21 drugs, while other compounds had no or minimal effect on cell growth. We thus focused on bortezomib and examined its growth inhibitory properties against nine canine malignant melanoma cell lines (CMM-1, CMM-2, ChMC, KMeC, LMeC, OMJ, OMS, OMK, and NML). Bortezomib inhibited the growth of all cell lines with calculated IC50 values of 3.5~5.6 nM.
Animal experiment [1]:
Animal models	Nude athymic mice
Dosage form	0.8 mg/kg; intravenous injection
Applications	The in vivo growth inhibitory activity of bortezomib against CMM-1 cells was evaluated using a xenograft mouse model. Bortezomib significantly suppressed the growth of tumours after Day 4 of treatment (P < 0.01, control vs. bortezomib). Tumours from the bortezomib-treated mice showed a significant decrease in mitotic index compared to controls (P
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Ito K, Kobayashi M, Kuroki S, et al. The proteasome inhibitor bortezomib inhibits the growth of canine malignant melanoma cells in vitro and in vivo[J]. The Veterinary Journal, 2013, 198(3): 577-582.