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ABT-737: THE SMALL BCL-2 INHIBITOR

by Selleckchem | Mar 13 2012

BCL-2 INHIBITION AND ITS IMPLICATIONS:

Bcl-2 family of proteins are a series of regulator proteins governing the pro-survival pathway [1]. Characteristically Bcl-2 has been discovered to be over expressed in a variety of tumor types such small cell lung cancer [2], melanoma [3], prostate [4] and breast cancer [5]. The concept of targeted chemotherapy is to focus drug inhibition against a target that is over expressed in the cancer cell in comparison to normal cellular material; Bcl-2 is a clear target for inhibition. Over expression of this protein disrupts the regulation of the intrinsic apoptotic pathway, creating chemotherapeutic resistance. By inhibiting the sequestering of pro-apoptotic proteins by the Bcl-2 family (anti-apoptotic proteins) normal apoptotic processes can be utilized to trigger tumor cell death [6]. Significantly there have been several now molecules introduced into the clinic in recent years which target Bcl-2 and have demonstrated clear benefits in chemotherapeutic action [7]. One of these small molecules is ABT-737, while others are Navitoclax (ABT-263), Obatoclax (GX15-070) and TW-37.

ABT-737 Chemical Structure

PROPERTIES AND MECHANISM OF ABT-737:

ABT-737 Bcl-2 inhibitor is a compound used to mimic the efficiency of molecules targeting the BH3 domain [8]. ABT-737 IC50’s inhibition of Bcl-2 range from to 2 -12 mM across a wide variety of cancer xenographs, indicating a broad spectrum of efficacy for this molecule. By inhibiting phosphorylation Bcl-2 the downstream mechanisms of MCL-1 is down regulated. This induces the natural process of apoptosis to occur, caused tumor reduction. ABT-737 has been shown to have no effect in tumor types with an over expression of MCL-1 [9], confirming its mechanism of action. [10]

ABT-737 - Preclinical Research

ABT-737 has been reported as been effecting in the inhibition of hematopoietic cell lines, in overcoming resistance in Burkit’s Lymphona [11], overcoming resistance in solid tumors [12] , in small cell lung cancer [13] and also in malignant glioma’s [14]. One interesting fact that has been reported is that ABT-737 appears to as effective in Hypoxia conditions compared to normoixa conditions[15]; which has far reach consequences in the treatment of pancreatic and solid tumor cancer.

ABT-737 has been investigated in combination with a wide variety of chemotherapy agents and other small molecule inhibitors. It has been reported that ABT-737 is synergistic when combined with a JAK-1 inhibitor.[16] In addition ABT-737 has sensitized resistant cell lines to the action of GDC-0941 [17], Sorafenib [18], Fenretinide [19], gemcitabine [20], actinomycin D [21] and ABT-263[22] to name but a few of the combinations tested. These investigation lead to the conclusion that the Bcl-2 inhibitor, ABT-737, was sufficiently potent to progress to clinical trial status.

ABT-737 CLINICAL TRIALS:

To date no phase 1 or phase 2 trials have been reported for the single use of ABT-737 but in combination treatments it has demonstrated potent anti-myeloma activity with Melphalan and Dexamethasone [19;23]. This small molecule represents a large step in the future of overcoming drug resistances via the intrinsic apoptotic pathway and warrants further clinical investigation.

ABT-737 – Physical properties and availability

ABT-737 structure has been elucidated through X-ray crystallography and it shows its potential for Bcl-2 inhibition by being a BH-3 mimetic [6]. ABT-737 is poorly soluble in water or ethanol but ABT-solubility in DMSO is sufficient to give a 5 mg/ml solution. Comercially research grade buy ABT-737’s can obtained with ABT-737 price range of between $230 -450 for different ABT-737 suppliers. ABT-737 stability is indicated as being greater than 2 years for the dry solid when stored at -20°C. No information is available on stability of ABT-737 in solution or in medium preparations.

References

1. McKenna SL, Cotter TG. Functional aspects of apoptosis in hematopoiesis and consequences of failure. Adv Cancer Res 1997; 71:121-164.

2. Wesarg E, Hoffarth S et al. Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int J Cancer 2007; 121(11):2387-2394.

3. Maeda M, Miura Y et al. Immunological changes in mesothelioma patients and their experimental detection. Clin Med Circ Respirat Pulm Med 2008; 2:11-17.

4. Lee EC, Tenniswood M. Programmed cell death and survival pathways in prostate cancer cells. Arch Androl 2004; 50(1):27-32.

5. Jameel JK, Rao VS et al. Radioresistance in carcinoma of the breast. Breast 2004; 13(6):452-460.

6. Richardson A, Kaye SB. Pharmacological inhibition of the Bcl-2 family of apoptosis regulators as cancer therapy. Curr Mol Pharmacol 2008; 1(3):244-254.

7. Azmi AS, Mohammad RM. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol 2009; 218(1):13-21.

8. Lee EF, Czabotar PE et al. Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family. Cell Death Differ 2007; 14(9):1711-1713.

9. Yecies D, Carlson NE et al. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010; 115(16):3304-3313.

10. Konopleva M, Contractor R et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10(5):375-388.

11. Pujals A, Renouf B et al. Treatment with a BH3 mimetic overcomes the resistance of latency III EBV (+) cells to p53-mediated apoptosis. Cell Death Dis 2011; 2:e184.

12. Cragg MS, Jansen ES et al. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest 2008; 118(11):3651-3659.

13. Hann CL, Daniel VC et al. Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. Cancer Res 2008; 68(7):2321-2328.

14. Voss V, Senft C et al. The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 2010; 8(7):1002-1016.

15. Klymenko T, Brandenburg M et al. The Novel Bcl-2 Inhibitor ABT-737 Is More Effective in Hypoxia and Is Able to Reverse Hypoxia-Induced Drug Resistance in Neuroblastoma Cells. Mol Cancer Ther 2011; 10(12):2373-2383.

16. Will B, Siddiqi T et al. Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. Blood 2010; 115(14):2901-2909.

17. Zheng L, Yang W et al. GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1. Cancer Lett 2011; 309(1):27-36.

18. Zhang W, Konopleva M et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 2008; 22(4):808-818.

19. Fang H, Harned TM et al. Synergistic activity of fenretinide and the Bcl-2 family protein inhibitor ABT-737 against human neuroblastoma. Clin Cancer Res 2011; 17(22):7093-7104.

20. Zhang C, Cai TY et al. Synergistic antitumor activity of gemcitabine and ABT-737 in vitro and in vivo through disrupting the interaction of USP9X and Mcl-1. Mol Cancer Ther 2011; 10(7):1264-1275.

21. Xu H, Krystal GW. Actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 against small cell lung cancer cell lines. Clin Cancer Res 2010; 16(17):4392-4400.

22. Yamaguchi R, Janssen E et al. Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy. PLoS One 2011; 6(9):e24102.

23. Trudel S, Stewart AK et al. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res 2007; 13(2 Pt 1):621-629.