期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 14, 页码 5637-5648出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00753
关键词
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资金
- Watkins Chair of Obstetrics and Gynecology
- Richard Silverman-CMIDD Research Award
- Australian National Health and Medical Research Council [GNT1016460]
- Robert H. Lurie Comprehensive Cancer Center
- Lynn Sage Foundation through Northwestern Memorial Foundation
- Chicago Biomedical Consortium
- Searle Funds at The Chicago Community Trust
- Cancer Center Support Grant from the National Cancer Institute [P30 CA060553]
- Northwestern University [HD076188]
Activin belongs to the TGF beta superfamily, which is associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways holds promise as a therapeutic approach to these diseases. A small-molecule ligand-binding groove was identified in the interface between the two activin beta A subunits and was used for a virtual high-throughput in silico Screening of the ZINC database to identify hits. Thirty-nine compounds without significant toxicity were tested in two well-established activin assays: FSH beta transcription and HepG2 cell apoptosis. This screening workflow resulted in two lead compounds: NUCC-474 and NUCC-555. These potential activin antagonists were then shown to inhibit activin A-mediated cell proliferation in ex vivo ovary cultures. In vivo testing showed that our most potent compound (NUCC-555) caused a dose-dependent decrease in FSH levels in ovariectomized mice. The Blitz competition binding assay confirmed target binding of NUCC-555 to the activin A:ActRII that disrupts the activin A:ActRII complex's binding with ALK4-ECD-Fc in a dose-dependent manner. The NUCC-555 also specifically binds to activin A compared with other TGF beta superfamily member myostatin (GDR). These data demonstrate a new in silico-based strategy for identifying small-molecule activin antagonist's. Our approach is the first to identify a first-in-class small-molecule antagonist of activin binding to ALK4, which opens a completely new approach to inhibiting the activity of TGF beta receptor superfamily members, in addition, the lead compound can serve as a starting point for lead optimization toward the goal of a compound that may be effective in activin-mediated diseases.
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