ABT-263: THE BH-3 MIMETIC

ABT-263 – Introduction:

ABT-263 is a small molecule Bcl-2/Bcl-XL inhibitor marketed by Abbott laboratories under the generic name of Navitoclax [1]. Similar in nature to ABT-737, also marketed by Abbott laboratories, ABT-263 inhibits the anti – intrinsic apoptotic pathway via the BH3 domain [2;3]. Bcl-2/Bcl-XL bind with pro-apoptotic proteins (BID) with the single BH3 domain and thereby regulate the apoptotic process. However, it has been observed in numerous cancer types that Bcl-2 is over expressed which leads to the survival of cells that would normally be removed via apoptosis [4]. ABT-263 Bcl-2 inhibitor have been demonstrated to be effective against small cell lung cancer xenographs [5], acute lymphoblastic leukemia [6;7] and hematologic tumors.[8]

ABT-263 - Preclinical investigations:

Initial success was demonstrate for ABT-263 in small cell lung cancer xenographs and cell lines where a significant effect was observed at a variety of dosing levels and for several different schedules. Interestingly, halting of tumor growth was significantly apparent even after treatment had been stopped [5]. An important study investigated the genetic profile of sensitive compared to resistant xenographs, identifying a subset of biomarkers which indicated sensitivity to ABT-263, this would important clinical implications.[9]

ABT-263, like it competitor ABT-737, appears to most effective in combination therapy with other small molecule inhibitors or with more traditional chemotherapy. Synergistic effects have been documented with YM155 [10], rapamycin [11], taxanes [12], etoposide, vincristine, VAP, ritximab, bortezomib and cyclophosphamide [8;13]. Resistance to ABT-263 activity has been linked to albumin binding in the systemic circulation [14] and to overexpression of Mcl-1 [12;15] In a panel of pediatric tumors ABT-263 was not effect as a single agent against solid tumors but was highly significant against acute lymphocytic leukemia [16]

ABT-263 - CLINICAL TRIALS:

ABT-263 is being developed in several phase 1 clinical trials, several are still ongoing and no interim report is available. However, in patients with SCLC 20% demonstrated either a partial response of over 2 years or stable disease for unto one year. Interestingly comparison of genetic biomarkers or responders to non responders revealed Pro-gastrin releasing peptide (pro-GRP) as correlating to Bcl-2 amplification and to significant changes in tumor volume. The success of ABT-263 was used as the basis for the assessment that ABT-263 should progress to phase 2 and phase 3 testing.

ABT-263 clinical trials are currently being conducted at phase 2 and phase 3 by Abbott and Genetech in SCLC, interim reports have not yet been published but recruitment is still ongoing indicating a positive outlook for this drug. In chronic lymphocytic leukemia a phase 1 trial is ongoing and the reported completion date is October 2012 (NCT00868413). Several phase 2 trials are also ongoing with patients of the disease groups non-hodgkin's lymphoma (NHL), chronic lymphoid leukemia (CLL), follicular, mantle cell and peripheral T-cell lymphoma. To

ABT-263 – Physical properties and Availability

Determination of the ABT-263 structure enabled the developed of the large scale chemical synthesis, ABT-263 is cheaper and easier of manufacture compared to its rival ABT-737 [17]. Bioavailability of ABT-263 has been determined in pre-clinical animal models and is estimated as being between 20 – 50% depending heavily on the formulation. This low bioavailability can be linked to the molecule’s very poor solubility in aqueous solutions although ABT-263 solubility in organic solvents like chloroform, DMSO, and methanol is estimated at 2-10 mg/ml. The ABT-263 IC50 is lower than many comparable drugs (> 1 μmol/L) for various cell lines tested.

Commercial availability of research grade ABT-263 price varies between ABT-263 supplier and ranges from $200 – 300 for 5 mg. ABT-263 stability is reported as being for 2 years when kept in the solid state at -20°C, no indication is given for stability in solution.

References

1. Tse C, Shoemaker AR et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008; 68(9):3421-3428.

2. Park CM, Bruncko M et al. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 2008; 51(21):6902-6915.

3. Vogler M, Dinsdale D et al. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 2009; 16(3):360-367.

4. Chonghaile TN, Letai A. Mimicking the BH3 domain to kill cancer cells. Oncogene 2008; 27 Suppl 1:S149-S157.

5. Shoemaker AR, Mitten MJ et al. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res 2008; 14(11):3268-3277.

6. Smith MA. Update on developmental therapeutics for acute lymphoblastic leukemia. Curr Hematol Malig Rep 2009; 4(3):175-182.

7. O'Connor OA. Novel agents in development for peripheral T-cell lymphoma. Semin Hematol 2010; 47 Suppl 1:S11-S14.

8. Ackler S, Mitten MJ et al. The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo. Cancer Chemother Pharmacol 2010; 66(5):869-880.

9. Tahir SK, Wass J et al. Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines. Mol Cancer Ther 2010; 9(3):545-557.

10. Tang H, Shao H et al. Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263. Biochem Pharmacol 2011; 82(9):1066-1072.

11. Ackler S, Xiao Y et al. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Ther 2008; 7(10):3265-3274.

12. Tan N, Malek M et al. Navitoclax enhances the efficacy of taxanes in non-small cell lung cancer models. Clin Cancer Res 2011; 17(6):1394-1404.

13. Chen J, Jin S et al. The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo. Mol Cancer Ther 2011; 10(12):2340-2349.

14. Vogler M, Furdas SD et al. Diminished sensitivity of chronic lymphocytic leukemia cells to ABT-737 and ABT-263 due to albumin binding in blood. Clin Cancer Res 2010; 16(16):4217-4225.

15. 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.

16. Lock R, Carol H et al. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer 2008; 50(6):1181-1189.

17. Wang GJ, Zhang HS et al. An efficient synthesis of ABT-263, a novel inhibitor of antiapoptotic Bcl-2 proteins. Synthesis-Stuttgart 2008;(15):2398-2404.

Related Products

Cat.No.	Product Name	Information
S1001	Navitoclax (ABT-263)	Navitoclax (ABT-263) is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki of ≤ 0.5 nM, ≤1 nM and ≤1 nM in cell-free assays, but binds more weakly to Mcl-1 and A1. Phase 2.
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.

Related Targets

Bcl-2