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Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain

Iyer, Divyaanka and Vartak, Supriya V and Mishra, Archita and Goldsmith, Gunaseelan and Kumar, Sujeet and Srivastava, Mrinal and Hegde, Mahesh and Gopalakrishnan, Vidya and Glenn, Mark and Velusamy, Mahesh and Choudhary, Bibha and Kalakonda, Nagesh and Karki, Subhas S and Surolia, Avadhesha and Raghavan, Sathees C (2016) Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain. In: FEBS JOURNAL, 283 (18). pp. 3408-3437.

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Official URL: http://dx.doi.org/10.1111/febs.13815


The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines. BCL2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico, biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL2, but not to other antiapoptotic BCL2 family members viz., BCL-xL, BCL2A1 etc. Interestingly, biophysical studies showed that BH1 domain deletion mutant demonstrated similar to 67-fold reduction in BCL2-Disarib interaction, while it was only similar to 20-fold in the case of BH3 deletion mutant, suggesting predominant involvement of the BH1 domain for Disarib binding. Thus, we report identification of a novel BCL2 inhibitor with a unique mechanism of BCL2 inhibition, as opposed to the well-studied BH3 domain targeting.

Item Type: Journal Article
Publication: FEBS JOURNAL
Additional Information: Copy right for this article belongs to the WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre: Division of Biological Sciences > Biochemistry
Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 07 Dec 2016 05:15
Last Modified: 07 Dec 2016 05:15
URI: http://eprints.iisc.ac.in/id/eprint/55487

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