BCL-2 INHIBITORS HARMONIZING APOPTOSIS

by Selleckchem | Sep 18 2012

IMPROPER REGULATION OF BCL-2 PATHWAY IN TUMORS:
Bcl-2 protein is abbreviated on basis of chromosomal translocations for the B-cell lymphoma 2 is a major apoptosis regulatory protein [1] and is seen to be associated with it in the follicular lymphoma. Bcl-2 protein along with its other family members keeps a tight check on balancing the cell growth and apoptosis of the cells by keeping an interaction with each other. Any disturbance in the homeostatic balance between apoptosis and growth of cells usually results in the aberrations associated with various types of cancers. Hence using the Bcl-2 inhibitors to achieve Bcl-2 inhibition seems to be an attractive and promising strategy for the treatment of many types of cancers [2]. Different Bcl-2 antagonists are designed on the basis of this strategy among them some are showing promising results at the pre-clinical and clinical levels. As the decrease in apoptosis is a key feature of the development of some sort of cancer, so it was not very surprising to find an association between the Bcl-2 gene, breast cancer, melanoma, prostate cancer and lung carcinomas along with the neurodegenerative problems like autoimmune disorders and schizophrenia. Despite of its role in tumorigenesis, the Bcl-2 gene has been concerned in producing resistance in cancer cell lines against the traditional treatment strategies.

BCL-2 INHIBITORS PHARMACOLOGY:
Some Bcl-2 family members are antiapoptotic by nature for example Bcl-w, Bcl-2 and Bcl-xL etc so for the proper induction of effective apoptosis, neutralization of such members and also other members i.e., Bcl2A1 and Mcl-1 is very essential. Hence there are some Bcl-2 signaling pathway inhibitors which are being used for this specific purpose while there are also some non-specific inhibitors or pan inhibitors which have shown promising results. Various Bcl-2 inhibitors specific in nature are more famously known than the others are ABT-737 and ABT-263 [3] along with Obatoclax or GX15-070, Oblimersen sodium [4] and AT-101. To easily get these bcl-2 inhibiting drugs is not a big issue as the researchers can buy these inhibitors for their laboratory and research utilization at very reasonable prices from respective suppliers. Some of the Bcl-2 kinase inhibitors are designed by mimicking the BH-3 protein and are known as BH-3 mimetics [5] and these mimetics stimulate the Bcl-2 induced proapoptotic signaling pathway. A lot of these inhibitors are found to have a great potential of causing anti-tumor activity as a stimulating agent while some of them work well in synergistic way with the other molecules.

BCL-2 INHIBITORS: CLINICAL TRIALS
ABT-263 and one of its analog ABT-737 are the famous of all examples of Bcl-2 inhibiting drugs in the clinical studies. These inhibiting drugs are developed by the abbot laboratories and exhibited remarkably effective results when tested in different in vivo and in vitro preclinical assessments to check their anti-tumor activity. One of the examples of BH-3 mimetic drug molecule is ABT-737 [6] that has been used against prostate cancer, lymphoma and lung cancer while another BH-3 mimetic named ABT-263 was used against solid tumors and its different pharmacokinetic properties were thoroughly studied in clinical trial phase I and phase II against the patients of lymphoid cancers [7]. Obatoclax is another drug also known as GX15-070 which has shown its effectiveness in inhibiting the apoptotic resistance induced by MCL1 [8] in clinical assessment phase II against the small-cell lung cancer patients.

REFERENCES:
1. Tsujimoto Y, e.a., Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science, 1984.
2. Vogler M, e.a., Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ., 2009.
3. Oltersdorf T, e.a., An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 2005.
4. Konopleva M, e.a., Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res, 2008.
5. Gillissen B, e.a., Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway. EMBO J, 2003.
6. Delft MF, e.a., The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell, 2006.
7. Wilson WH, e.a., A phase 1/2a study evaluating the safety, pharmacokinetics and efficacy of ABT-263 in subjects with refractory or relapsed lymphoid malignancies. Blood, 2007.
8. Nguyen M, e.a., Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA, 2007.

Cat.No.	Product Name	Information
S1002	ABT-737	ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM in cell-free assays, respectively; no inhibition observed against Mcl-1, Bcl-B or Bfl-1. ABT-737 induces mitochondrial pathway apoptosis and mitophagy. Phase 2.
S1001	Navitoclax (ABT-263)	Navitoclax (ABT-263) is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with K_i of ≤ 0.5 nM, ≤1 nM and ≤1 nM in cell-free assays, but binds more weakly to Mcl-1 and A1. Phase 2.
S1057	Obatoclax Mesylate (GX15-070)	Obatoclax Mesylate (GX15-070) is an antagonist of Bcl-2 with K_i of 0.22 μM in a cell-free assay, can assist in overcoming MCL-1 mediated resistance to apoptosis.