Design, Synthesis and Evaluation of a Novel Bcl-2/Mcl-1 Inhibitor

Xiaodong Zhang

doi:10.54097/65cgsb32

Authors

Xiaodong Zhang

DOI:

https://doi.org/10.54097/65cgsb32

Keywords:

Apoptosis, Bcl-2/Mcl-1 protein, Inhibitor, Structure-based drug design

Abstract

Bcl-2 and Mcl-1 are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. Structure-based drug design was utilized to develop a novel, 1-oxo-1H-phenalene-2,3-dicarbonitrile (OPD)-based small molecule inhibitor (S2) of Bcl-2/Mcl-1, which was synthesized readily by nucleophilic substitution reaction and click reaction. S2 exhibited potent binding capability to both Bcl-2 (Ki=0.60±0.20) and Mcl-1 (Ki=0.87±0.25 μM). Furthermore, S2 exhibited potent lethality on Hela cells.

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References

[1] Hanahan, D.; Weinberg, R. A. The hallmarks of cancer. Cell 2000, 100, pp. 57−70.

[2] Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 2011, 144, pp. 646−674.

[3] Reed, J. C. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 1994, 124, pp.1−6.

[4] Igney, F. H.; Krammer, P. H. Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2002, 2, pp. 277−288.

[5] J.D. Leverson, H. Zhang, J. Chen, et al., Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax), Cell Death Dis. 2015, 6, pp. e1590.

[6] L. Bai, J. Chen, D. McEachern, et al., BM-1197: a novel and specific Bcl-2/Bcl-xl inhibitor inducing complete and long-lasting tumor regression in vivo, PLoS One 2014, 9, pp. e99404.

[7] A.J. Souers, J.D. Leverson, E.R. Boghaert, et al., ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets, Nat. Med. 2013,19, pp. 202-208.

[8] E. Varin, C. Denoyelle, E. Brotin, et al., Downregulation of Bcl-xL and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy, Carcinogenesis 2010, 31, pp. 984-993.

[9] T. Song, X. Li, X. Chang, X. Liang, Y. Zhao, G. Wu, S. Xie, P. Su, Z. Wu, Y. Feng, Z. Zhang, Bioorg. Med. Chem. 2013, 21, pp. 11.

[10] Z. Zhang, P. Su, X. Li, T. Song, G. Chai, X. Yu, K. Zhang, Arch. Pharm. 2015, 348, pp. 89.

[11] J. Cheng, T.J. Deming, Pept. Mater. 2011, 310, pp. 1–26.