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Chemical Biology

Introduction

A human body consists of 60 trillion cells comprised of lipids, proteins, and nucleic acids. Small molecule compounds, such as vitamins, steroid hormones, and heme, modulate the intricate and sophisticated apparatus in cells. Some of the daily over-the-counter medicines are also made of small molecule compounds. However, exactly how small-molecule compounds exert their activities is not fully elucidated. Even among popular, marketed drugs, there are many for which the mechanism of action is unclear.

Small molecule compounds are extremely useful tools for understanding complex biological systems. Elucidating how a compound affects the body can lead to the elucidation of unknown molecular networks in the body involving target proteins. In the case of pharmaceutical compounds, this knowledge can also lead to drug repositioning and new drug development. Chemical biology is an interdisciplinary research field that addresses these issues, and we are conducting research aimed at drug development using our unique interaction analysis technology (proteomics) and genetic screening technology.

Research methodology

One of the unique methods in our lab is a biochemical method using FG beads. Under the leadership of Professor Emeritus Hiroshi Handa, who retired in March 2012, our lab took on the challenge of developing a new research tool to elucidate the mechanism of action of small molecule compounds in vivo and developed FG beads, an excellent affinity chromatography carrier. FG beads are microparticles with a magnetic iron core (Fe₃O₄) and a particle size of 140-200 nm. By using FG beads immobilized with small molecule compounds of interest as ligands, target factors can be purified in one step and in a short time. With a very low background and high yield, the beads are chemically stable and can be surface modified (introduction of carboxylic acids, amino groups, etc.) quite easily. Since FG beads are also magnetic, they can be purified by magnetic separation without using a centrifuge. FG beads have been successfully commercialized and are available from Tamagawa Seiki Co. Our chemical biology studies with FG beads have revealed important and interesting mechanisms woven by various small molecule compounds. We are also developing distance-dependent in situ biotinylation as a new method to explore and identify molecular interactions that are difficult to approach by conventional affinity chromatography. In addition, we are also performing sgRNA library screens using CRISPR/Cas9 as a function-based genetic approach to complement interaction-based approaches.

Thalidomide research and a new direction in drug development

Undoubtedly, the most significant achievement of our research aimed at drug discovery so far is the identification of the thalidomide target protein. Thalidomide was developed in the 1950s as a hypnotic and sedative drug. Due to its teratogenic effect that was initially overlooked, many babies with limb deformities were born as a result of women taking thalidomide during early pregnancy. This is remembered as one of the worst drug disasters in history. Thalidomide research continued, however, and thalidomide was found to have excellent therapeutic effects against leprosy and multiple myeloma (a type of blood cancer), among others. As a result, thalidomide and its successors have come into the spotlight as commonly used drugs worldwide in this century. The mechanism of action of thalidomide was unknown for a long time, but in 2010, together with Professor Emeritus Hiroshi Handa and Dr. Takumi Ito, we discovered that the intracellular target of thalidomide is a protein called cereblon (CRBN), using FG bead technology, which brought a breakthrough in this research area.

Thalidomide and CRBN do not have just one drug-one target relationship, but have the potential to expand and develop into a new foundation for drug development. CRBN is a subunit of the E3 ubiquitin ligase complex CRL4^CRBN. It has become clear that thalidomide-related drugs alter its substrate specificity, inducing the ubiquitination and degradation of proteins that do not serve as substrates in the absence of the drugs (neosubstrates). In other words, thalidomide-related drugs seem to act as "molecular glues" bridging CRL4^CRBN and neo-substrates and induce the degradation of various neo-substrates, thereby exerting diverse drug effects. Thus, exploration and identification of neo-substrates for CRBN has become an important research issue in recent years. Since ubiquitination and degradation of different neo-substrates can be induced by slightly changing the molecular structure of thalidomide-related drugs, it is hoped that thalidomide-related drugs can target proteins that have not been considered as therapeutic targets before. Therefore, this research area is attracting much attention as a new direction in drug development.

As described above, thalidomide-related drugs have great potential and are an area of intense research for us. We continue our research in the hope that our research will lead to healthier lives for people.

Research