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

Iyer, D, Vartak, SV, Mishra, A, Goldsmith, G, Kumar, S, Srivastava, M, Hegde, M, Gopalakrishnan, V, Glenn, M, Velusamy, M
et al (show 5 more authors) (2016) Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain. The Federation of European Biochemical Societies (FEBS) Journal, 283 (18). pp. 3408-3437.

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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.

Item Type: Article
Uncontrolled Keywords: apoptosis, cancer therapeutics, cell death, chemotherapy, genomic instability, leukemia, molecular docking, small molecule inhibitor
Depositing User: Symplectic Admin
Date Deposited: 16 May 2017 10:29
Last Modified: 19 Jan 2023 07:04
DOI: 10.1111/febs.13815
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