| Added by | mollevi |
|---|---|
| Last modified by | Nathalie Bonnefoy |
| Group name | EquipeNB |
| Item Type | Journal Article |
| Title | Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737 |
| Creator | Mathieu et al. |
| Author | A. L. Mathieu |
| Author | O. Sperandio |
| Author | V. Pottiez |
| Author | S. Balzarin |
| Author | A. Herledan |
| Author | J. O. Elkaim |
| Author | M. L. Fogeron |
| Author | C. Piveteau |
| Author | S. Dassonneville |
| Author | B. Deprez |
| Author | B. O. Villoutreix |
| Author | N. Bonnefoy |
| Author | F. Leroux |
| Abstract | One approach currently being developed in anticancer drug discovery is to search for small compounds capable of occupying and blocking the hydrophobic pocket of anti-apoptotic Bcl-2 family members necessary for interacting with pro-apoptotic proteins. Such an approach led to the discovery of several compounds, such as ABT-737 (which interacts with Bcl-2, Bcl-xl, and Bcl-w) or the latest one, ABT-199, that selectively targets Bcl-2 protein. The efficacy of those compounds is, however, limited by the expression of two other anti-apoptotic Bcl-2 members, Mcl-1 and Bfl-1. Based on the role of Bfl-1 in cancer, especially in chemoresistance associated with its overexpression in B-cell malignancies, we searched for modulators of protein-protein interaction through a high-throughput screening of a designed chemical library with relaxed drug-like properties to identify small molecules targeting Bfl-1 anti-apoptotic protein. We found two compounds that display electrophilic functions, interact with Bfl-1, inhibit Bfl-1 protective activity, and promote cell death of malignant B cells. Of particular interest, we observed a synergistic effect of those compounds with ABT-737 in Bfl-1 overexpressing lymphoma cell lines. Our results provide the basis for the development of Bfl-1 specific antagonists for antitumor therapies. |
| Publication | J Biomol Screen |
| Volume | 19 |
| Pages | 1035-1046 |
| Date | May 8 2014 |
| Journal Abbr | Journal of biomolecular screening |
| DOI | 10.1177/1087057114534070 |
| ISSN | 1552-454X (Electronic) 1087-0571 (Linking) |
| Tags | first-last-corresponding, original |
| Date Added | 2018/11/14 - 12:04:32 |
| Date Modified | 2019/05/28 - 21:25:47 |
| Notes and Attachments | (Note) (Note) 24809353 (Attachment) |
Institut de Recherche en Cancérologie de
