Research Summary † †

Create New World of Bioactive Synthetic Molecules: New ways to use, New Shapes, New sizes.

Gene expression modulator, “wrenchnolol.”　Regulation of gene expression by transcription factors touches every process in eukaryotic biology. Our research on transcription factors has resulted in a number of publications [e.g., Science (1997); PNAS (2002)].　From a chemical library, our laboratory discovered a small molecule that controls the gene-activating function of transcription factor, ESX, and named it “adamanolol” [JACS (2003)]. Optimization of adamanolol led to the design of “wrenchnolol” [JACS (2004)]. This wrench-shaped molecule represents the first synthetic organic molecule that directly controls gene expression, by blocking the protein-protein interaction of a transcription factor.

Small molecule transcription factor mimic. Our research demonstrated that wrenchnolol conjugated with a DNA-binding polyamide molecule mimics the activation domain of a transcription factor. For the first time, we showed that it is possible to create a functional transcription factor out of completely organic components [JACS (2004); JACS (2009)]. The molecular weights of naturally occurring transcription factors are typically 50-100 KDa. The development of small-molecule transcription factors successfully demonstrates that a large protein important in biological processes can be mimicked by a synthetic small molecule.

Chromeceptin. Hepatocellular carcinomas, or liver cancers, often overproduce insulin-like growth factor (IGF), resulting in uncontrolled growth. We discovered a small molecule, “chromeceptin” (94G6), which inhibits the IGF-dependent growth of liver cancers [JBC (2003)]. Analysis of chromeceptin led to the discovery of a new intracellular signaling pathway that regulates IGF and insulin signals [Chem. Biol. (2006)]. Chromeceptin is now commercially available as a research tool from the Sigma Chemicals and other chemical companies worldwide.

Fatostatin. We discovered this unique bioactive molecule from a chemical library almost by chance [JBC (2003)]. Molecular biological analyses showed that the simple molecule, which we named “fatostatin,” specifically turns off genes responsible for making fat in cells and animals.　Fatostatin binds a protein, called SCAP, and inhibits the activation of SREBP transcription factor, a master regulator of fat synthesis in human cells. Mice treated with fatostatin do not get fat, even with excessive food consumption. Fatostatin represents the first non-cholesterol small molecule that selectively blocks the activation of SREBP [Chem. Biol. (2009)]. Fatostatin or its analogs are expected to serve as tools for controlling fat synthesis.　These results attracted attention from the lay public and were reported broadly in national and international newspapers, including all of the major Japanese newspapers.

Fishing rod technology. The most effective way to use small molecules for biological investigation is to identify their targets. However, target identification has always been a technical hurdle in the field. We have developed a “fishing rod” approach, which boosts the affinity purification of the protein targets of bioactive small molecules [JACS (2007)]. 　The technology has now been used by five drug companies for their drug discovery programs. Use of this technology by the P.I.’s own laboratory allowed the successful isolation of the targets of fatostatin [Chem. Biol. (2009)] and the marine natural product, aurilide [Chem. Biol. (2011)].

Adhesamine. We discovered a small molecule that boosts the attachment and growth of human cells. This molecule represents the first non-peptidic molecule that induces physiologically relevant, normal cell adhesion [Chem. Biol. (2009)]. The molecule named “adhesamine” targets selective cell-surface glycosaminoglycans, especially heparan sulfate. Adhesamine has been licensed out and is now commercially available for a range of applications.

Mitochondorial surface-specific fluorescent probe. Small molecule probes have made significant contributions to biomedical research. However, many cellular components remain to be explored by small molecule probes. We have discovered the first fluorescent probe specific for mitochondrial surfaces [Angew. Chem. Int. Ed. (2011)]. Interestingly, this molecule is converted to be fluorescent inside cells.