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BCL-2 INHIBITOR – SMALL YET EFFECTIVE

by Selleckchem | Mar 13 2012

INHIBITION OF BCL-2 PROTEINS:

Apoptosis is the natural system for the removal of cellular material from the body. This could be due to damage by invasion, age or injury. There are two mechanisms which regulate this process, the Intrinsic and the Extrinsic pathways. The extrinsic pathway is a cascade of signal originating from outside the cell via death receptors on the cellular membrane. The intrinsic pathway is initiated within the cell whereby pro-apoptotic proteins are released to activate the caspase cascade from the mitochondria. Part of the caspase cascade is the family of Bcl-2 proteins which regulate the process towards apoptosis or survival. Bcl-2 family consists of anti-apoptotic members such as Bcl-2, Mcl-1, Bcl-XL and Bcl2a1, other members are the pro-apoptotic proteins such as BAX, BAK, BAD, BIM, PUMA, BID, BIK, NOXA and BMF. In many forms of cancer it has been demonstrated that Bcl-2 is over expressed such as lung, breast, prostate, renal, ovarian and glioblastoma cancer, melanoma and leukemia are the highest report over expressers of Bcl-2 [1].

Targeted chemotherapy utilizes the differences of unregulated tumor cell growth factors compared to situation in normal cells. Different types of cell have a different balance of factors making generalizations for systemic treatment problematic. Targeting the intrinsic pathway one series of small molecules focus on the over expression of Bcl-2 and in the past decade this type of inhibitor has been extensively researched. Various structurally related molecules have been developed based on the design of the BH3 domain linking the pro-apoptotic and pro-survival proteins of the Bcl-2 family. Inhibition of the BH3 domain restores the cellular apoptotic regulation to a degree, and signaling cascades are triggered eventually causing apoptosis.

VARIOUS BCL-2 INHIBITORS AS THERAPEUTIC DRUGS:

ABT-737 – ABT-737 is a small molecule marketed by Abbott laboratories that was designed via computer simulation to mimic the action of molecules targeting the BH3 domain. APT-737 is a broad spectrum inhibitor with significant inhibitory effects observed outside of the Bcl-2 family of proteins. This and the very poor solubility make the molecule difficult to formulated into an effective treatment. [1-3]

ABT-263 - ABT-263 is a small molecule Bcl-2/Bcl-XL inhibitor marketed by Abbott laboratories under the generic name of Navitoclax. Similar in nature to ABT-737, also marketed by Abbott laboratories, ABT-263 inhibits the intrinsic anti–apoptotic pathway via the BH3 domain. Unlike ABT-737 this molecule is soluble in ethanolic solutions and as such an oral treatment is possible. Without the requirement of intravenous treatment care the cost of this therapy is significantly reduced. Patients can be treated in an outpatient clinic for assessment for the majority of the treatment course.[4-8]

Gossypol - Derived from the cotton plant Gossypol is a polyphenolic compound consisting of 6 phenolic hydroxyl groups and two aldehydic groups. It is chemically reactive undergoing ozonolysis, oxidation, and methylation to form active derivatives. It has been determine to active in a wide range of biological processes which include anticancer properties. Structurally Gossypol is chiral consisting of two entiomers with different biological activities. The anticancer activity is linked to the R form of this molecule but it is ineffective as single drug but has demonstrated synergistic properties with traditional chemotherapeutic treatments. However, toxicological problems exist with this molecule limiting its clinical use. [9-13]

TW-37 – Tw-37 is a pan-Bcl-2 inhibitor with infinity for Bcl-2. Bcl-XL and Mcl-1. As an inhibitor of both the pro-apoptotic and pro-survival proteins TW-37 is active against endothelial cells of oral mucosa in patients with head and neck cancer. Not effective as a single agent this molecule has demonstrated some synergism with cisplatin enhancing tumor collapse. TW-37 has also demonstrated some activity towards pancreatic cancer in vitro warranting further investigation [14;15]

Chelerythrine – chelerythrine is a benzophenanthridine alkaloid derived the plant chelidonium majus. It demonstrated potent inhibitory activity toward Protein kinase C (PKC) and it has been identified as an inhibitor of Bcl-XL. [16;17] Limited clinical details are reported and no clinical trial are listed for this drug.

HA14-1 – Discovered by computer simulation of the predicted structure of the Bcl-2 protein HA14-1 induces apoptosis in acute myeloid leukemia cells lines which over express Bcl-2. While clinically this molecule doesn’t appear to be effective this molecule is being used as a chemical probe to define the mechanism of Bcl-2 inhibition and as a bases for drug design with Bcl-2 inhibitor as the target.[18-22]

Antimycin A – antimycin is a chemical piscicide acting against cytochrome C reductase inhibiting oxidation of Ubiquinol. It is widely used in the fish industry. Recently, however, computational evidence linked Antimycin A to the binding domain of Bcl-XL indicating an alternative mechanism to that originally derived. Antimycin A is not traditionally used as a chemotherapy agent and research is only just starting to investigate its potential.[23-26]

Obatoclax (GX15-070) – GX15-070 is a pan-Bcl-2 inhibitor with targeting against both pro-apoptotic and pro-survival proteins. Obatoclax overcomes Mcl-1 over expression resistance but increase toxicity of the treatment linked to the intrinic pathaway and to non-mechanism effects present problems associated with this molecule.[27]

Apogossypolone (ApoG2) – using gossypol as a starting molecule successive derivatives were developed and tested for Bcl-2 activity. Apogossypolone (ApoG2) is a derivative of gossypol and demonstrated activity towards the Bcl-2 family of proteins. Preclinical investigations have demostrated pan-Bcl-2 activity with specificity towards Bcl-2, Bcl-XL and Mcl-1. Further preclinical work has demonstrated clear apoptotic effects in prosate and nasal cancer cell lines sufficient to indicate further investigation clinically.[28]

Many of these Bcl-2 pathway inhibitors are commonly available commercially as research chemicals and one can buy Bcl-2 inhibitors from a variety of sources.

BCl-2 INHIBITORS IN CANCER CLINICAL TRIALS:

Inhibition of Bcl-2 has been considered as a target for chemotherapy for a decade or more but it was not until the mechanisms of action were determined that small molecules demonstrating in vitro specificity were moved to the clinical setting. Bcl-2 cancer studies involving ABT-263 have demonstrated it to be the most successfully of all the Bcl-2 inhibitors on the market by virtue of being are orally administered treatment. ABT-263 has under gone phase 1 trials demonstrating acceptable toxicity profiles and significant tumor apoptotic effects. Typically Bcl-2 inhibitors have demonstrated synergism with more traditional chemotherapy rather than as single agents. However, other than Bcl-2 clinical trials for lymphoma xenographs (TW-37), lymphoid malignancies (ABT-263) and SCLC (ABT-263) Bcl-2 inhibitors have yet to make a significant clinical mark.

Related to Bcl-2 inhibitors are two antisense oligonucleotides which target not Bcl-2 itself but the formation of Bcl-2 within the cell. By reducing the expression of Bcl-2 a similar effect to inhibition can be observed. Geneasense and G3139 [29] are the two notable treatments available, with pre-clinical work being done on induction of apoptosis in colorectal [30] and prostate cancers [31] Pharmacokinetic studies have not been reported and are required prior to testing in the clinical setting

References

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30. Moreira JN, Santos A et al. Bcl-2-targeted antisense therapy (Oblimersen sodium): towards clinical reality. Rev Recent Clin Trials 2006; 1(3):217-235.

31 Chi KN, Gleave ME. Antisense approaches in prostate cancer. Expert Opin Biol Ther 2004; 4(6):927-936.