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Identification of a novel BCL 2‐specific inhibitor that binds predominantly to the BH 1 domain
Author(s) -
Iyer Divyaanka,
Vartak Supriya V.,
Mishra Archita,
Goldsmith Gunaseelan,
Kumar Sujeet,
Srivastava Mrinal,
Hegde Mahesh,
Gopalakrishnan Vidya,
Glenn Mark,
Velusamy Mahesh,
Choudhary Bibha,
Kalakonda Nagesh,
Karki Subhas S.,
Surolia Avadhesha,
Raghavan Sathees C.
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13815
Subject(s) - identification (biology) , domain (mathematical analysis) , chemistry , computational biology , microbiology and biotechnology , biology , mathematics , mathematical analysis , botany
The antiapoptotic protein BCL 2 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 BCL 2 inhibitor. Disarib showed selective cytotoxicity in BCL 2 high cancer cell lines, and CLL patient primary cells, as compared to BCL 2 low cell lines. BCL 2 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 BCL 2, but not to other antiapoptotic BCL 2 family members viz., BCL ‐ xL , BCL 2A1 etc. Interestingly, biophysical studies showed that BH 1 domain deletion mutant demonstrated ~ 67‐fold reduction in BCL 2‐Disarib interaction, while it was only ~ 20‐fold in the case of BH 3 deletion mutant, suggesting predominant involvement of the BH 1 domain for Disarib binding. Thus, we report identification of a novel BCL 2 inhibitor with a unique mechanism of BCL 2 inhibition, as opposed to the well‐studied BH 3 domain targeting.