WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 100100
CAS#: 179324-69-7
Description: Bortezomib is a dipeptide boronic acid analogue with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy.
MedKoo Cat#: 100100
Name: Bortezomib
CAS#: 179324-69-7
Chemical Formula: C19H25BN4O4
Exact Mass: 384.19689
Molecular Weight: 384.24
Elemental Analysis: C, 59.39; H, 6.56; B, 2.81; N, 14.58; O, 16.66
Synonym: PS-341; PS 341; PS341; LDP 341; LDP-341 ;LDP341; MLN341; MLN-341; MLN 341. US brand name: VELCADE.
IUPAC/Chemical Name: ((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)boronic acid
InChi Key: GXJABQQUPOEUTA-RDJZCZTQSA-N
InChi Code: 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
SMILES Code: CC(C)C[C@@H](B(O)O)NC([C@@H](NC(C1=NC=CN=C1)=O)CC2=CC=CC=C2)=O
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Bortezomib (PS-341, Velcade, LDP-341, MLM341, NSC 681239) is a potent 20S proteasome inhibitor with Ki of 0.6 nM. |
| In vitro activity: | The average growth inhibition of 50% (GI50) value for PS-341 across the entire NCI cell panel was 7 nm. Moreover, when 13 dipeptide proteasome inhibitors from the boronate series were examined, a strong correlation (Pearson coefficient, r2 = 0.92) was noted after plotting Ki versus GI50 values (Fig. 1). This finding associates the intrinsic potency of this class of compounds with their antiproliferative activity in cell culture assays, confirming their activity through a biological target, the proteasome. Using the NCI’s algorithm COMPARE (16) , we compared the “fingerprint” for PS-341-induced cytotoxicity to the historical file of 60,000 compounds and found it to be unique, with little correlation to other “standard” or investigational agents. In addition, PS-341 was shown to penetrate into cells and inhibit proteasome-mediated intracellular proteolysis of long-lived proteins with a concentration that inhibited 50% of the proteolysis (IC50) of ∼0.1 μm (data not shown). In the in vitro screen the prostate tumor PC-3 cell line (22) was shown to be sensitive to the antiproliferative effects of PS-341. To examine the potential mechanism(s) of proteasome inhibitor-induced cytotoxicity, PS-341 was studied in detail in this prostate cell line. Numerous proteins control cell cycle progression, including the tumor suppressor p53 and the CDK inhibitors p21 and p27 (12) . PC-3 cells are p53 null (23) , and hence, this protein is not required for PS-341-induced cytotoxicity in this cell line. In fact, PS-341 was demonstrated to be cytotoxic in multiple cell lines in the NCI screen, independent of p53 status (data not shown). Protein levels of p21 were measured to exemplify the activity of PS-341 in cells. Although very little p21 protein was detected in untreated cells, levels were significantly increased with 10 nm PS-341 (Fig. 2A) occurring 24 h after drug addition. The increase in p21 protein levels could be detected 4 h after PS-341 treatment (data not shown). The increase in p21 led to an inhibition in the activity but not the levels of CDK-4 after 8 h (data not shown). Reference: Cancer Res. 1999 Jun 1;59(11):2615-22. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10363983 |
| In vivo activity: | Initial activity of bortezomib (PS-341) was examined in vivo with a hollow fiber assay (29), which recorded very good activity for PS-341 and a series of analogues (data not shown). This gave impetus to examine antitumor activity for PS-341 in human xenografts. For example, s.c. implantation of human PC-3 tumor cells into nude mice elicits a large tumor that is eventually lethal. PS-341 was administered to mice injected with PC-3 cells when the tumors became palpable (>300 mm3). Two studies were undertaken. First, mice bearing PC-3 tumors were injected with PS-341 (0.3 or 1.0 mg/kg) i.v. once weekly for 4 weeks, and tumor volumes were recorded. Weekly i.v. treatment with PS-341 (1.0 mg/kg) resulted in a significant decrease in tumor growth ∼60% (P < 0.05), as determined by measurement of tumor volume. The lower dose of PS-341 (0.3 mg/kg) produced a 16% decrease in tumor volume but did not reach significance (Fig. 4A). PS-341 significantly decreased the tumor volume although distribution of the compound to the skin is limited (see below). To further explore the anticancer utility of PS-341, the drug was administered directly into PC-3 tumors in a second study. On 4 consecutive days, PS-341 (1.0 mg/kg) was administered (in 10 μl) into established PC-3 tumors, and results clearly showed a dramatic decrease in tumor burden (Fig. 4B). In addition to the large decrease in tumor volume (70%), two of five mice (40%) had no detectable tumors at the end of the study. At well-tolerated doses, treatment with PS-341 clearly suppressed tumor growth. These data highlight the full antitumor potential of PS-341. Similar effects have been observed in other murine tumors and human xenograft tumors (data not shown). No adverse effects of drug treatment were noted during any of these studies. Reference: Cancer Res. 1999 Jun 1;59(11):2615-22. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10363983 |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 76.0 | 197.79 |
The following data is based on the product molecular weight 384.24 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. PMID: 10363983. 2. Pérez-Galán P, Roué G, Villamor N, Montserrat E, Campo E, Colomer D. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006 Jan 1;107(1):257-64. doi: 10.1182/blood-2005-05-2091. Epub 2005 Sep 15. PMID: 16166592. |
| In vitro protocol: | 1. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. PMID: 10363983. 2. Pérez-Galán P, Roué G, Villamor N, Montserrat E, Campo E, Colomer D. The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood. 2006 Jan 1;107(1):257-64. doi: 10.1182/blood-2005-05-2091. Epub 2005 Sep 15. PMID: 16166592. |
| In vivo protocol: | 1. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. PMID: 10363983. |
1: Bockorny M, Chakravarty S, Schulman P, Bockorny B, Bona R. Severe heart failure after bortezomib treatment in a patient with multiple myeloma: a case report and review of the literature. Acta Haematol. 2012;128(4):244-7. doi: 10.1159/000340050. Epub 2012 Sep 4. Review. PubMed PMID: 22964848.
2: Broyl A, Jongen JL, Sonneveld P. General aspects and mechanisms of peripheral neuropathy associated with bortezomib in patients with newly diagnosed multiple myeloma. Semin Hematol. 2012 Jul;49(3):249-57. doi: 10.1053/j.seminhematol.2012.04.001. Review. PubMed PMID: 22726548.
3: Kapoor P, Ramakrishnan V, Rajkumar SV. Bortezomib combination therapy in multiple myeloma. Semin Hematol. 2012 Jul;49(3):228-42. doi: 10.1053/j.seminhematol.2012.04.010. Review. PubMed PMID: 22726546.
4: Sekiguchi Y, Shirane S, Imai H, Sugimoto K, Wakabayashi M, Sawada T, Chigira N, Ichikawa K, Komatsu N, Noguchi M. Response to low-dose bortezomib in plasma cell leukemia patients with malignant pleural effusion and ascites: a case report and a review of the literature. Intern Med. 2012;51(11):1393-8. Epub 2012 Jun 1. Review. PubMed PMID: 22687849.
5: Barosi G, Merlini G, Billio A, Boccadoro M, Corradini P, Marchetti M, Massaia M, Tosi P, Palumbo A, Cavo M, Tura S. SIE, SIES, GITMO evidence-based guidelines on novel agents (thalidomide, bortezomib, and lenalidomide) in the treatment of multiple myeloma. Ann Hematol. 2012 Jun;91(6):875-88. doi: 10.1007/s00277-012-1445-y. Epub 2012 Apr 4. Review. PubMed PMID: 22476884.
6: Sureshkumar KK, Hussain SM, Marcus RJ, Ko TY, Khan AS, Tom K, Vivas CA, Parris G, Jasnosz KM, Thai NL. Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation. Clin Nephrol. 2012 Mar;77(3):246-53. Review. PubMed PMID: 22377258.
7: Zangari M, Terpos E, Zhan F, Tricot G. Impact of bortezomib on bone health in myeloma: a review of current evidence. Cancer Treat Rev. 2012 Dec;38(8):968-80. doi: 10.1016/j.ctrv.2011.12.007. Epub 2012 Jan 9. Review. PubMed PMID: 22226939.
8: Mujtaba T, Dou QP. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med. 2011 Dec;12(67):471-80. Review. PubMed PMID: 22204764.
9: Picot J, Cooper K, Bryant J, Clegg AJ. The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation. Health Technol Assess. 2011 Dec;15(41):1-204. doi: 10.3310/hta15410. Review. PubMed PMID: 22146234.
10: Delforge M. Bortezomib for previously untreated multiple myeloma. Expert Opin Pharmacother. 2011 Nov;12(16):2553-64. doi: 10.1517/14656566.2011.622266. Epub 2011 Sep 23. Review. PubMed PMID: 21942881.
Bortezomib is "indicated" (recommended) for single-agent use in the treatment of patients with multiple myeloma who have received at least two prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types.
Bortezomib (VELCADE®, formerly PS-341) was approved for the treatment of patients with relapsed or refractory multiple myeloma in May 2003 by the US Food and Drug Administration and in April 2004 by the Committee for Proprietary Medicinal Products of the European Union. In December 2006 the FDA approved Bortezomib for treatment of mantle cell lymphoma.
Bortezomib binds to the proteasome and does so "reversibly" (this is a chemical term that means that the bortezomib molecule can come free under different micro-cellular chemical conditions.) Normal healthy (non-cancer) cells are not as prone to damage from this binding after the Bortezomib comes off, as cancer cells are. Malignant cells suffer a breakdown even after inhibition of the proteasome for a short time.
According to http://en.wikipedia.org/wiki/Bortezomib, Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, which soon changed its name to ProScript. After promising preclinical results, the drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite in turn was bought by Millennium Pharmaceuticals in October 1999. At this point in time, the project had low priority amongst other projects at the company. This changed significantly when one of the first volunteers to receive the drug in the clinical trial achieved a complete response and was still alive four years later. At the time this was a remarkable result. Later clinical experimentation indicates the possibility of a complete response in 15% of patients in a similar condition, when treated with bortezomib. In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.
According to http://en.wikipedia.org/wiki/Bortezomib, Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, which soon changed its name to ProScript. After promising preclinical results, the drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite in turn was bought by Millennium Pharmaceuticals in October 1999. At this point in time, the project had low priority amongst other projects at the company. This changed significantly when one of the first volunteers to receive the drug in the clinical trial achieved a complete response and was still alive four years later. At the time this was a remarkable result. Later clinical experimentation indicates the possibility of a complete response in 15% of patients in a similar condition, when treated with bortezomib. In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.
