BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins.
J Med Chem
; 53(10): 4166-76, 2010 May 27.
Article
in En
| MEDLINE
| ID: mdl-20443627
ABSTRACT
In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here the synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 0.31, 0.32, 0.20, and 0.62 microM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC(50) values of 0.13, 0.56, and 0.049 microM, respectively, and shows little cytotoxicity against bax(-/-)bak(-/-) cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gossypol
/
Apoptosis
/
Proto-Oncogene Proteins c-bcl-2
/
Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2010
Document type:
Article
Affiliation country:
United States