Obatoclax mesylate (GX15-070)Catalog No. A10665

Quick Overview

Bcl-2 homology domain-3 (BH3) mimetic,antagonize all antiapoptotic Bcl-2 family proteins (average IC50, 3 umol/L), including Mcl-1 (IC50, 2.9 umol/L) and Bfl-1 (IC50, 5 umol/L).
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Obatoclax mesylate (GX15-070)

Product Information
Catalog Num A10665
M. Wt 413.5
Formula C20H19N3O.CH4O3S
Solubility DMSO>83mg/mL Water<1mg/mL Ethanol<1mg/mL
Purity >98%
Storage at -20°C 2 years
CAS No. 803712-79-0
Synonyms N/A
Chemical Name 2-[2-[(3,5-Dimethyl-1H-pyrrol-2-yl)methylene]-3-methoxy-2H-pyrrol-5-yl]-1H-indole methanesulfonate
SMILES Code CC1=CC(=C(N1)/C=C/2\C(=C/C(=C\3/C=C4C=CC=CC4=N3)/N2)OC)C.CS(=O)(=O)O

Biological activity
Introduction
Bcl-2 homology domain-3 (BH3) mimetic,antagonize all antiapoptotic Bcl-2 family proteins (average IC50, 3 umol/L), including Mcl-1 (IC50, 2.9 umol/L) and Bfl-1 (IC50, 5 umol/L).
Targets
Bcl-2 (Cell-free assay)
0.22 μM(Ki)
Solubility
Solubility (25C) * In vitro DMSO 83 mg/mL (200.73 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Adooq 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.

Biological Activity

Description Obatoclax (GX15-070) is an antagonist of Bcl-2 with Ki of 0.22 μM, can assist in overcoming MCL-1 mediated resistance to apoptosis. Phase 1/2.
Targets Bcl-2
IC50 0.22 μM (Ki) [1]
In vitro Obatoclax completely inhibits Bak recovery of Mcl-1 at 5 μM in SK-Mel5 cells and overcomes resistance to ABT-373-induced apoptosis conferred by Mcl-1 in KB/Bcl-2 cells. [1] Obatoclax is a BH3 mimetic which binds to a broad spectrum of Bcl-2 family members, including Bcl-2, Bcl-xL, and Mcl-1. Obatoclax uniquely displaces BH3 domains by activation of the pocket of Mcl-1 followed by a triggering of apoptosis mediated by oligomerization of Bak and release of cytochrome c. Obatoclax is sensitive to Bcl-xL in cell lines lacking it or showing low expression. It shows low cytotoxicity to Mcl-1, Bcl-2, and Bcl-xL in all the strongly-expressed cell lines. Obatoclax inhibits multiple myeloma (MM) cell lines (KMS12PE, KMS18, MY5, etc.) with IC50 values ranging from 52 to 1100 nM and the inhibition is umimpaired even in the presence of IL-6 or IGF-1, which are resistance to cytotoxic agents, at a concentration of 150 nM. Obatoclax enhances the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. [2] Obatoclax potentiates TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-mediated apoptosis by unsequestering Bak and Bim from Bcl-2/Bcl-xL or Mcl-1 proteins in PANC-1 and BxPC-3 cells. [3]
In vivo Obatoclax also exhibits high antitumor activity in SCID mice bearing human C33A cerivical carcinoma tumors at a dose of 0.5 mg/kg. [1]
Features Obatoclax is a potential first-in-class small molecule antagonist of Bcl-2 designed to inhibit all relevant members of the Bcl-2 family of proteins, including the dominant member, Mcl-1.

Protocol(Only for Reference)

Kinase Assay: [1]

Bcl-2 Binding affinity calculation A predicted binding affinity for Obatoclax binding to BCL-2 is calculated using the SIE scoring function. [4] As a control in determining the reliability of the calculation, predicted binding affinities Ki) are calculated for a set of 12 small molecules with experimentally measured binding affinities to BCL-2.

Cell Assay: [2]

Cell lines Human MM cells (HMCLs), peripheral blood lymphocytes (PBLs), bone marrow stromal cells (BMSCs)
Concentrations ~10 μM
Incubation Time 48-72 hours
Method Obatoclax is dissolved in DMSO at a stock concentration of 5 mM. Cell viability is assayed by MTT. Human MM cells (HMCLs), peripheral blood lymphocytes (PBLs), bone marrow stromal cells (BMSCs) are seeded in 96-well plates at a density of 2 × 104 per well for HMCLs or 5~10 × 103 for PBLs. Various concentrations of Obatoclax are added to the cells, with or without IGF-1 (50 ng/mL) or IL-6 (10 ng/mL). Cells are incubated for 48-72 hours and cell viability is determined.

Animal Study: [1]

Animal Models Female BALB/c or CB17 SCID/SCID mice bearing SW480, C33A, PC3, and 4T1 cells are used.
Formulation Obatoclax (tartrate salt) is formulated in 9.6% polyethylene glycol 300, 0.4% polysorbate 20, and 5% dextrose; while for the 4T1 tumor model, Obatoclax is formulated at a concentration of 0.6 mg/mL in 9.48% polyethylene glycol, 0.38% polysorbate 20, 1.2 mg/mL mannitol, and 5% dextrose.
Dosages 0.0313, 0.25, 0.5 and 2 mg/kg
Administration Administered intravenously (tail vein) once a day

1

Reference
1. Nguyen M, et al. Proc Natl Acad Sci, 2007, 104(49), 19512-191517.
2. Trudel S, et al. Blood, 2009, 113(2), 299-305.
3. Huang S, et al. Clin Cancer Res, 2009, 15 (1), 150-159.
4. Naim M, et al. J Chem Inf Model, 2007, 47(1), 122-133.

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00918931 Terminated Leukemia|Systemic Mastocytosis M.D. Anderson Cancer Center|Gemin X 2009-06 Phase 2
NCT00933985 Active, not recruiting Acute Undifferentiated Leukemia|Blastic Phase Chronic Myelogenous Leukemia|Childhood Burkitt Lymphoma|Childhood Chronic Myelogenous Leukemia|Cutaneous B-cell Non-Hodgkin Lymphoma etc. National Cancer Institute (NCI) 2009-06 Phase 1
NCT01150656 Active, not recruiting Leukemia National Cancer Institute (NCI)|Children's Oncology Group 2010-06
NCT01238146 Withdrawn Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue|Nodal Marginal Zone B-cell Lymphoma|Recurrent Grade 1 Follicular Lymphoma|Recurrent Grade 2 Follicular Lymphoma etc. National Cancer Institute (NCI) 2010-10 Phase 1|Phase 2
NCT01563601 Withdrawn Extensive-stage Small Cell Lung Cancer Teva Pharmaceutical Industries|Cephalon 2012-08 Phase 3
Return Policy Contact information
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