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Novel BCL2 inhibitor, Disarib induces apoptosis by disruption of BCL2-BAK interaction

Vartak, V Supriya and Lyer, Divyaanka and Santhoshkumar, T R and Sharma, Sheetal and Mishra, Archita and Goldsmith, Gunaseelan and Srivastava, Amrinal and Srivastava, Shikha and Karki, S Subhas and Surolia, Avadhesha and Choudhary, Bibha and Raghavan, S Sathees (2017) Novel BCL2 inhibitor, Disarib induces apoptosis by disruption of BCL2-BAK interaction. In: BIOCHEMICAL PHARMACOLOGY, 131 . pp. 16-28.

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Official URL: http://dx.doi.org/10.1016/j.bcp.2017.02.015


Apoptosis is a highly regulated pathway of programmed cell death relying on the fine balance between pro and antiapoptotic binding partners. Overexpression of the antiapoptotic protein BCL2 in several cancers makes it an ideal target for chemotherapy, with minimum side effects. In one of our previous studies, we designed, synthesized and characterized Disarib, a BCL2-specific small molecule inhibitor. Interestingly, Disarib showed a novel mode of BCL2 inhibition, by predominantly binding to its BH1 domain, as compared to the BH3-specific action of other known BCL2 inhibitors. Here, we investigate the mechanism by which Disarib induces cell death, upon binding to BCL2. We find that Disarib specifically disrupted the BCL2-BAK interaction, but not that of BCL2-BAX or other members of the proapoptotic family such as PUMA and BIM, in vitro. Biochemical and biophysical studies demonstrate Disarib-induced inhibition of BCL2-BAK interaction with a Ki of 12.76 nM. Genetic knockout cells of BAK/BAX and double knockout (DKO) cells confirmed a BAK-specific action of Disarib, thereby facilitating apoptosis. Importantly, intracellular FRET in BAK/BAX single and double knockout cells demonstrated BCL2-BAK disruption, and activation of intrinsic pathway of apoptosis upon Disarib treatment. Thus, we report a unique mechanism of action of a BCL2 inhibitor, Disarib, by specifically targeting the interaction of BCL2-BAK, while sparing that of other proapoptotic binding partners. (C) 2017 Elsevier Inc. All rights reserved.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the PERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
Department/Centre: Division of Biological Sciences > Biochemistry
Division of Biological Sciences > Molecular Biophysics Unit
Depositing User: Id for Latest eprints
Date Deposited: 20 May 2017 05:22
Last Modified: 20 May 2017 05:22
URI: http://eprints.iisc.ac.in/id/eprint/56893

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