Novel tertiary sulfonamides as potent anti-cancer agents
- Bioorg Med Chem. 2018 Aug 15;26(15):4441-4451. doi: 10.1016/j.bmc.2018.07.042.
- 1. Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA.
- 2. Cardiovascular Institute and Department of Medicine, Stanford University, 300 Pasteur Dr., MC-5501, Stanford, CA 94305, USA.
- 3. Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA. Electronic address: [email protected].
For adult women in the United States, breast Cancer is the most prevalent form of Cancer. Compounds that target dysregulated signal transduction can be efficacious anti-cancer therapies. A prominent signaling pathway frequently dysregulated in breast Cancer cells is the Wingless-related integration site (Wnt) pathway. The purpose of the work was to optimize a "hit" from a screening campaign. 76,000 compounds were tested in a Wnt transcription assay and revealed potent and reproducible "hit," compound 1. Medicinal chemistry optimization of 1 led to more potent and drug-like molecules, 19, 24 and 25 (i.e., Wnt pathway IC50 values = 11, 18 and 7 nM, respectively). The principal results showed compounds 19, 24 and 25 were potent anti-proliferative agents in breast Cancer cell lines, MCF-7 (i.e., IC50 values = 10, 7 and 4 nM, respectively) and MDA-MB 231 (i.e., IC50 values = 13, 13 and 16 nM, respectively). Compound 19 synergized anti-proliferation with chemotherapeutic Doxorubicin in vitro. A major conclusion was that compound 19 enhanced anti-proliferation of Doxorubicin in vitro and in a xenograft animal model of breast Cancer.