CEP-18770 (Delanzomib)

Catalog No.S1157

CEP-18770 (Delanzomib) is an orally active inhibitor of the chymotrypsin-like activity of proteasome with IC50 of 3.8 nM, with only marginal inhibition of the tryptic and peptidylglutamyl activities of the proteosome. Phase 1/2.

Price Stock Quantity  
USD 147 In stock
USD 997 In stock
Bulk Inquiry

Massive Discount Available

Free Overnight Delivery on all orders over $ 500.

CEP-18770 (Delanzomib) Chemical Structure

CEP-18770 (Delanzomib) Chemical Structure
Molecular Weight: 413.28

Validation & Quality Control

Quality Control & MSDS

Product Information

  • Compare Proteasome Inhibitors
    Compare Proteasome Products
  • Research Area

Product Description

Biological Activity

Description CEP-18770 (Delanzomib) is an orally active inhibitor of the chymotrypsin-like activity of proteasome with IC50 of 3.8 nM, with only marginal inhibition of the tryptic and peptidylglutamyl activities of the proteosome. Phase 1/2.
Targets Chymotrypsin-like proteasome [1]
IC50 3.8 nM
In vitro CEP-18770 demonstrates marginal prevention of the tryptic and peptidyl gultamyl activities of the protesome. The IC50 values of CEP-18770 are similar to those of bortezomib, with the chymotryptic and caspase-like activities being inhibited at low-nanomolar concentrations.[1] CEP-18770 inhibits A2780 ovarian cancer cells, PC3 prostate cancer, H460, LoVo colon cancer, RPMI8226 multiple myeloma cancer and HS-Sultan anaplastic non-Hodgkin lymphoma with IC50 values of 13.7, 22.2, 34.2 11.3, 5.6 and 8.2 nM, respectively.[1] CEP-18770 blocks the ubiquitin-proteasome pathway in several MM and in the chronic myelogenous leukemia cell line, K562. CEP-18770 causes an accumulation of ubiquitinated proteins over 4 to 8 hours with a profile similar to that observed after bortezomib treatment.[1] IκBα degradation is completely blocked by pretreatment with CEP-18770. CEP-18770 significantly inhibits high levels of NF-κB activity in both RPMI-8226 and U266 cells. The time- and concentration-dependent suppression of NF-kB DNA-binding activity in MM cell lines by CEP-18770 leads to a decrease of expression of several NF-κB-modulated genes mediating the growth and survival of tumor cells including IkBα itself, the X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), the pro-inflammatory cytokines TNF-α and interleukin-1β (IL-1β), the intracellular adhesion molecule (ICAM1), and the pro-angiogeneic factor vascular endothelial growth factor. [1] The expression of these NF-κB–mediated genes and their modulation by bortezomib are associated with more favorable clinical responsiveness to this agent, highlighting their potential prognostic value in response to CEP-18770 exposure. [1] The proapoptotic activity of CEP-18770 against MM is not limited solely to tumor-derived MM cell lines, but extends to primary MM explants from relapsed or refractory patients including those previously treated with bortezomib. [1] In addition, the combination of CEP-18770 with melphalan or bortezomib produces synergistic inhibition of MM cell viability in vitro.[2]
In vivo CEP-18770 reveals sustained dose-related relative tumor weight inhibition. CEP-18770 leads to dose-related complete tumor regressions, as compared to bortezomib treatment, which results in a 50% incidence of CR at its maximally tolerated dose (MTD) of 1.2 mg/kg intravenously. [1] In contrast to bortezomib, CEP-18770 reveals dose-related increase in the incidence of tumor-free mice by the completion of these studies (120 days after tumor transplantation). Oral administration of CEP-18770 produces a marked decrease in tumor weight and notable dose-related incidence of complete tumor regression with minimal changes in animal body weight over the course of the 120 day studies. [1]When compared to bortezomib, equiactive doses of CEP-18770 reveal a greater and more sustained dose-related inhibition of tumor proteasome activity, corresponding temporarily with maximum induction of caspase-3 and 7 activity.[1] The maximum apoptotic signal is 2.5 fold greater for CEP-18770 versus bortezomib. In contrast, proteasome inhibition profiles of CEP-18870 and bortezomib are comparable in the normal peripheral mouse tissues examined (liver, lungs, whole blood, and brain [no activity]) in both their magnitude and their duration.[1] No proteasome inhibition is detected in brain tissue at any time point for either CEP-18770 or bortezomib. In MM xenograft models, the addition of CEP-18770 to melphalan completely preventes the growth of both melphalan-sensitive or melphalan-resistant tumours. [1] The combination of CEP-18770 and bortezomib leads to complete regression of bortezomib-sensitive tumours and markedly delays progression of bortezomib-resistant tumours compared to treatment with either agent alone. Single agent CEP-18770 PO also shows marked anti-MM effects in these xenograft models[1]
Features

Protocol(Only for Reference)

Kinase Assay: [3]

Probing proteasome activity in cell extracts Human multiple myeloma cells are washed twice with cold phosphate-buffered saline, pelleted and lysed with one volume of glass beads (<106 microns, acid-washed) and an equal volume of homogenization buffer (50 mM Tris (pH 7.4), 1 mM dithiothreitol, 5 mM MgCl2, 2 mM ATP and 250 mM sucrose) by vortexing at high speed for 15-30 min at 4 °C. Beads, membrane fractions, nuclei and cell debris are then removed from the supernatant by centrifugation at 16,000g for 5 min. The protein content of extracts is quantitated using the Bradford assay. Proteasome activity is assayed as described below. Equal amounts (typically 60 g) of protein are denatured by boiling in reducing sample buffer, separated by 12.5% SDS-PAGE and electrotransferred onto polyvinylidene difluoride (PVDF) membranes. Immunoblotting is performed using a dansyl-sulfonamidohexanoyl polyclonal antibody (1:7,500, rabbit) and horseradish peroxidase–coupled goat or swine anti-rabbit secondary antibody followed by enhanced chemiluminescence.

Cell Assay: [1]

Cell lines HMEC and TEC cells
Concentrations 0-100 nM
Incubation Time 6 hours
Method HMEC and TEC cells are seeded into 24-well plates at a density of 104 cells/well in DMEM supplemented with 5% FCS. After incubation with proteasome inhibitors (48 hours), cells are washed, air dried, and stained with crystal violet as described. Cell number is determined, in duplicate samples, on the basis of a standard curve obtained with known cell numbers. All experiments are performed in triplicate. In vitro formation of capillary-like structures is studied on cells (4 × 104 cells/well in DMEM supplemented with 5% FCS. After incubation with proteasome inhibitors (48 hours), cells are washed (cells/well in 24-well plates) and seeded onto Matrigel-coated wells in DMEM containing 0.25% BSA. HMEC and TEC cells (5 × 103 per well), suspended in 200 μL DMEM with 5% FCS (positive control), serum-free medium (negative control), are layered onto the Matrigel surface in the presence or absence of proteasome inhibitor CEP-18770. Cells are observed with a inverted microscope and experimental results are then recorded after a 6-hour incubation at 37 °C. Data is analyzed, as the mean (× 1 SD) of total length of capillary-like structures, by the Micro-Image system and is expressed as mm/field by the computer analysis system in 5 different fields at 100 × magnification in duplicated wells for 4 different experiments.

Animal Study: [1]

Animal Models Human MM RPMI 8226 subcutaneous xenograft model in SCID mice
Formulation In a solution of 3% DMSO
Dosages From 1.5 to 4 mg/kg, twice for 7 days to 4 weeks.
Administration Intravenously

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Piva R,et al. Blood. 2008,111(5),2765-2775.

[2] Sanchez E, et al. Br J Haematol. 2010,148(4),569-581.

view more

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01348919 Terminated Multiple Myeloma Cephalon|Teva Pharmaceutical Industries August 2011 Phase 1|Phase 2
NCT01023880 Terminated Multiple Myeloma Cephalon|Teva Pharmaceutical Industries January 2010 Phase 1|Phase 2
NCT00572637 Completed Solid Tumors|Lymphoma, Non-Hodgkin Ethical Oncology Science November 2007 Phase 1

Chemical Information

Download CEP-18770 (Delanzomib) SDF
Molecular Weight (MW) 413.28
Formula

C21H28BN3O5

CAS No. 847499-27-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 83 mg/mL (200.83 mM)
Ethanol 83 mg/mL (200.83 mM)
Water <1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (R)-1-((2S,3R)-3-hydroxy-2-(2-phenylpicolinamido)butanamido)-3-methylbutan-2-ylboronic acid

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

* Indicates a Required Field

Related Proteasome Products

  • VR23

    VR23 is a potent proteasome inhibitor with IC50 of 1 nM, 50-100 nM, and 3 μM for trypsin-like proteasomes, chymotrypsin-like proteasomes, and caspase-like proteasomes, respectively.

  • Calpeptin

    Calpeptin is a potent, cell-permeable calpain inhibitor with ID50 of 52 nM, 34 nM, 138 nM, and 40 nM for Calpain I (porcine erythrocytes), Calpain II (porcine kidney), Papainb, and Calpain I (human platelets), respectively.

  • Marimastat(BB-2516)

    Marimastat (BB-2516) is a broad spectrum matrix metalloprotease (MMP) inhibitor for MMP-9, MMP-1, MMP-2, MMP-14 and MMP-7 with IC50 of 3 nM, 5 nM, 6 nM, 9 nM and 13 nM, respectively. Phase 3.

  • MG-132

    MG-132 is an inhibitor of proteasome with IC50 of 100 nM in a cell-free assay, and also inhibits calpain with IC50 of 1.2 μM.

  • Bortezomib (PS-341)

    Bortezomib (PS-341) is a potent 20S proteasome inhibitor with Ki of 0.6 nM in a cell-free assay.

  • Carfilzomib (PR-171)

    Carfilzomib (PR-171) is an irreversible proteasome inhibitor with IC50 of <5 nM in ANBL-6 cells, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities.

  • Ixazomib (MLN2238)

    MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM in cell-free assays, respectively, also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites, with IC50 of 31 and 3500 nM. Phase 3.

    Features:A first-in-class proteasome inhibitor that has improved pharmacokinetics (PK), pharmacodynamics(PD), and antitumor activity in preclinical studies.

  • ONX-0914 (PR-957)

    ONX-0914 (PR-957) is a potent and selective immunoproteasome inhibitor with minimal cross-reactivity for the constitutive proteasome in a cell-free assay.

    Features:The first highly selective, small molecule inhibitor of the immunoproteasome. Potential use in cancer and autoimmune diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, and lupus).

  • MLN9708

    MLN9708 immediately hydrolyzed to MLN2238, the biologically active form, on exposure to aqueous solutions or plasma. MLN2238 inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50/Ki of 3.4 nM/0.93 nM in cell-free assays, less potent to β1 and little activity to β2. Phase 3.

    Features:The 1st oral proteasome inhibitor in early stage clinical trials for Multiple Myeloma.

  • Celastrol

    Celastrol is a potent proteasome inhibitor for the chymotrypsin-like activity of a purified 20S proteasome with IC50 of 2.5 μM.

    Features:A potent antioxidant and anti-inflammatory drug.

Recently Viewed Items

Tags: buy CEP-18770 (Delanzomib) | CEP-18770 (Delanzomib) supplier | purchase CEP-18770 (Delanzomib) | CEP-18770 (Delanzomib) cost | CEP-18770 (Delanzomib) manufacturer | order CEP-18770 (Delanzomib) | CEP-18770 (Delanzomib) distributor
×
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Contact Us