The trend of the world of drug discovery research and development recently has largely shifted from low molecular pharmaceuticals to biopharmaceuticals, and it is urgent to strengthen the future's drug discovery capability in Japan where there is not enough the R&D of biopharmaceuticals. The Center for Drug Discovery Research (CDDR) will contribute to the improvement of the capabilities for the drug discovery in Japan by establishing the new technology of the drug discovery platform for the biopharmaceuticals that is expected to expand its market in the future. <Two missions of CDDR> ① CDDR will aim for the development of the innovative medicines through research on methodologies and technologies to design pharmaceuticals of the new categories such as antibody pharmaceuticals, nucleic acid pharmaceuticals. ② As one of the technical support bases for "the drug discovery support network", CDDR plays a key role in bridging the research results found at Universities to the practical phase.

Changes in global medical economy drive continuous R&D reorganization which requires scientists to pursue not only scientific depth but also mindset and applied skill for creating novel values by assimilating external expertise. International assignment or oversea postdoc experiences instinctively provide people with opportunities to develop own expertise and abilities in a process that is out of one’s own comfort zone. In successful cases, the scientist sometimes demonstrates innovation by collaboration that may not happen by oneself, than just self-development. Nowadays, we’ve been asked to respond to the changes in modality diversification and methods in drug discovery and need to catch up and leverage advancement of biotherapeutics, drug delivery system, and cell therapy and so on, as well as classical small molecule discovery. Given this, global network is mandatory, and for this purpose so many Japanese researchers are visiting Boston to challenge new frontier of drug discovery which will be able to provide patients with curative therapeutic options.

Lysophospholipids are phospholipids with only one acyl chain. Depending on their head group and acyl chain, there are numerous lysophospholipid species in vivo. Recent studies have identified several GPCRs that specifically react with certain lysophospholipids. From the studies on these receptors, lysophospholipids have been shown to have critical roles in pathophysiological conditions. Lysophospholipids are simple in structure, which enable chemists to modify the structure of lysophospholipids chemically. Accordingly we succeeded in creating a potent agonist for LPA₃ , one GPCR for lysophosphatidic acid (LPA). Using the agonist we revealed a novel role of LPA₃ in endometrium in uterus.

Antibody-drug conjugates（ADCs）represent a promising drug class which expresses a wider therapeutic window than conventional chemotherapeutic agents by effecting efficient and specific drug delivery to antigen-expressing tumor cells. DS-8201a is a HER2-targeting ADC structurally composed of a humanized anti-HER2 antibody, enzymatically cleavable peptide-linker, and a novel topoisomerase 1 inhibitor. This ADC achieves a high drug-to-antibody-ratio（DAR 7 to 8）with homogeneous conjugation with the DNA topoisomerase 1 inhibitor. DS-8201a exhibited a HER2 expression-dependent cell growth inhibitory activity and induced a dose-dependent tumor regression in a HER2-positive gastric cancer NCI-N87 cell line derived xenograft（CDX）model and sufficient effectiveness in a T-DM1-nsensitive patient derived xenograft（PDX）model with low HER2 expression. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a’s being well tolerated in humans. These studies suggest that DS-8201a, a novel HER2-targeting ADC, may be more efficacious and have a broader patient population than T-DM1 in tumors which current anti-HER2 therapies are ineffective such as T-DM1 insensitive tumors and low HER2-expressing tumors.

For streamlining the development of oral drug products, it is quite important to assess the risk in oral drug absorption based on the physicochemical properties of candidate compounds. Especially, poorly water-soluble compounds often show nonlinear absorption kinetics due to the saturated solubility in the gastrointestinal tract. This might terminate the project because of the difficulty to obtain enough drug exposure in the blood for evaluating the toxicity and safety of the compound. As the method to avoid such risks, supersaturable formulations are now attracting a lot of attentions from pharmaceutical industries. By introducing such appropriate formulation technologies, it is possible to increase the efficacy in oral drug development.

Inducing protein degradation by small molecules attracts attention as a novel technology that could be applied for drug development in the next generation. The chemical protein knockdown technology was established by the development of epoch-making SNIPER and PROTAC compounds that induce ubiquitylation and proteasomal degradation of the target proteins. These compounds consist of two different ligands; one is for a target protein and the other for an E3 ubiquitin ligase, and they crosslink the target protein to an E3 ubiquitin ligase in the cells for ubiquitylation and degradation. Because of the modular structure, any intracellular proteins could be targeted for degradation by substituting the target ligands, which could also be applied to “undruggable” targets. In the United States, several bio-venture companies have been founded and they pursue clinical development of novel drugs based on the chemical protein knockdown technology.

Imaging mass spectrometry (imaging MS) is a molecular visualization method using mass spectrometry. Molecules are ionized directly on the sample surface, and then ions are introduced into a mass separation part. After ion detection, ion intensity map can be reconstructed. This information represents the molecular distribution on the sample surface. According to the principle, any molecular distributions will be available if ions are generated and detected in the mass spectrometer. Since imaging MS does not require radiation labels, distribution information of drug metabolites and biological metabolites before and after administration can be evaluated. Even if imaging MS requires invasion at tissue sampling, this method spotlights because of providing a lot of information without radiation labeling. In addition, quantitative capability in imaging MS is gradually improved. In this seminar, imaging MS as a novel pharmaco-imaging technique is explained.

We attended the 254^th ACS national meeting & exposition held in Washington D.C., America from 20 to 24, August, 2017. This international meeting is held twice a year. A lot of audiences from various countries around the world attended to this meeting. This meeting consists of many specialized fields of science. We focused on Division of Medicinal Chemistry (MEDI). In this report, some topics, especially in First time disclosure of drug candidates are described.