OBATOCLAX AGAINST BCL-2 PATHWAYS IN CANCER

Importance of Bcl-2 Pathway in Cancer:

The pro-survival protein Bcl-2 and its related family members activate pro-survival pathways in cancer that are often associated with uncontrolled proliferation of cancer cells. Apart from this direct effect, stress pathways are also reported to be converging with Bcl-2 signaling pathways which makes the development of various Bcl-2 inhibitors an attractive approach to target cancer by inducing mitochondrial apoptotic pathways [1].

Obatoclax’s Pharmacological Properties:

Obatoclax mesylate is also known as GX15-070 after its parent manufacturing company Genim X. The binding of this pan Bcl-2 family inhibitor to the anti-apoptotic members of Bcl-2 family would lead to release of Bax and Bak which would then permeabilize the outer mitochondrial membrane and result in releasing pro-apoptotic factors. Obatoclax structure shows the presence of an indole bipyrrole group. Obatoclax price is pretty high and an Obatoclax supplier would charge $500 for a 5 mg quantity of Obatoclax Bcl-2 inhibitor. Obatoclax IC50 value is 3.59 µM. Obatoclax solubility is poor in water and ethanol but can be gained in DMSO. One can buy Obatoclax easily for laboratory and research uses.

Obatoclax’s Mechanism of Action:

Obatoclax is reported to induce Bax mediated mitochondrial apoptosis [2] which can be Bak-dependent in some cases generating an anti-leukemic response. Obatoclax is reported to have good synergistic efficiency when given in combination with Histone Deacetylase Inhibitors (HDACi). It is also shown to induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling to mediate its pro-apoptotic actions. The Ser70 phosphorylation of Bcl-2 sensitizes CLL cells towards Obatoclax treatment.

Obatoclax in Research Studies:

The BH-3 mimetic drug Obatoclax induces autophagy in carcinoma cells [3], multiple myeloma cells (MM) and leukemia cells when given in combination with HDACi [4]. Cisplatin – Obatoclax combination sensitizes non-small cell lung cancer (NSCLC) towards Cisplatin treatment [5]. Its combination with Bortezomib increases its efficacy against in Mantle cell lymphoma cells [6].

Obatoclox’s Success at Clinical Levels:

This pan Bcl-2 inhibitor has been used in various Obatoclax clinical trials. Its pharmacokinetics was assessed by a phase I trial to find its appropriate dose in lymphoma and solid tumors [7]. In various phase I studies like those involving hematologic malignancies, treatment resistant Chronic lymphoid leukemia (CLL) patients [8] and solid tumors with Topotecan have generated remarkable results. Obatoclax was also used for the treatment of myelofibrosis and has been used in phase I and phase II trials against this cancer [9].

A combination study is assessing the effect of Obatoclax with Doxorubicin, Dexrazoxane or Vincristine in pediatric leukemia patients and against refractory or relapsed form of solid tumors patients enrolled in a phase I trial (ADVL0816). Obatoclax is also used against Systemic Mastocytosis in a phase I study (NCT00918931). Its combination efficacy with Bortezomib is being tested in relapsed or refractory form of Multiple Myeloma (MM) patients enrolled in phase I and II trials (NCT00719901) and with Fludarabine and Rituximab in previously treated CLL patients enrolled in a phase I trial (NCT00612612).

References:

1. Kang, M.H. et al, Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy. Clin Cancer Res, 2009.

2. Yang, J. et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science, 1997.

3. Pan, J. et al. The BH3-mimetic GX15-070 induces autophagy, potentiates the cytotoxicity of carboplatin and 5-fluorouracil in esophageal carcinoma cells. Cancer Letters, 2010.

4. Heidari, N.e.a., GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death and Disease, 2010.

5. Paik, P.K. et al, A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. Cancer Chemotherapy, 2010.

6. Trudel, S. et al, Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood, 2007.

7. Konopleva, M. et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Research, 2008.

8. Tsimberidou, A.M. et al. Treatment of fludarabine‐refractory chronic lymphocytic leukemia. Cancer, 2009.

9. Tefferi, A. Myelofibrosis with myeloid metaplasia. New England Journal of Medicine, 2000.

Related Products

Cat.No.	Product Name	Information
S1057	Obatoclax Mesylate (GX15-070)	Obatoclax Mesylate (GX15-070) is an antagonist of Bcl-2 with Ki of 0.22 μM in a cell-free assay, can assist in overcoming MCL-1 mediated resistance to apoptosis.

Related Targets

Bcl-2