The BINDS program (Basis for Supporting Innovative Drug Discovery and Life Science Research), has started since April 2017 to support innovative drug discovery and life science research. The objective of this program is to link the excellent research outcome in life science to the practical application of pharmaceuticals so on in our country, by providing and sharing key technological infrastructure, including synchrotron facilities at SPring-8 and the Photon Factory, cryo-electron microscopes, chemical compound libraries, and next-generation DNA sequencers. In addition, many specialists in state-of-the art technologies in the fields of structural biology, protein production, high-throughput screening (HTS) of chemical seeds to lead compounds, structural modifications and extensions, genome analysis, and in-silico screening, will support the drug discovery and life science research of researchers who submit their proposals to members of the BINDS program.

Many pharmaceutical companies focus on central nervous system (CNS) diseases to address the unmet medical needs. Given the complexity of CNS pharmacology and concurrent low success rate in CNS drug development, some companies are balancing their risks through collaborations. For instance, Shionogi entered a collaboration with Janssen for the development and commercialization of atabecestat, a BACE1 inhibitor, for the treatment of Alzheimer’s disease. In addition, both companies entered into a research collaboration for exploring back-up compounds to atabecestat. The author had the opportunity to join the collaboration as a medicinal chemist and to work at the Janssen research laboratories in Belgium. The experience of working in the Janssen facilities, and insights from the collaboration between Shionogi and Janssen will be described.

Lysosomal storage diseases are a group of metabolic diseases, caused by genetic deficiency of lysosomal hydrolase enzymes or their co-factors, that results in progressive accumulation of undigested lipids or glycolipids in the lysosomes of affected cells. Chaperone compounds bind to and stabilize the mutant enzyme protein and enhanced their residual activity in the patients’ cells. Initial development of this therapy was conducted in Japan. Small molecular chaperone compounds can be orally administered and can attenuate neurological manifestations. In this essay, I would like to describe our development of candidate chaperone compounds and the recent clinical applications of this therapy.

An antibody-drug conjugate (ADC) is a biologics that binds a drug to a monoclonal antibody. ADCs use antibodies to selectively deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. We discovered trastuzumab deruxtecan (T-DXd, DS-8201a) with the study of ADC drug-linker technology as the next-generation ADC drug that applied a camptothecin derivative, which is a DNA topoisomerase I inhibitor, to an anti-HER2 antibody. T-DXd achieves a high drug-to-antibody-ratio with homogeneous conjugation and has strong potency on heterogeneous tumors by the bystander effect and considers safety concerns in systemic circulation by drug-linker stability. T-DXd could provide a valuable therapy with a great potential to respond to breast cancer and other HER2-expression cancers in clinical settings. Phase II and III is ongoing for HER2-positive breast cancer, HER2-low breast cancer, HER2-positive gastric cancer and the other HER2-expressing cancers.

Cinacalcet hydrochloride is well-used for the treatment of secondary hyperparathyroidism as a CaSR agonist in dialysis patients. However, it is also known that cinacalcet has several issues such as adverse effects on the gastrointestinal tract (e.g., nausea and vomiting) and drug-drug interactions from strong CYP2D6 inhibition. We started the drug discovery efforts targeting CaSR agonists without the defects of cinacalcet, and it leaded the discovery of evocalcet. It shows excellent BA and does not inhibit CYPs such as 2D6. Evocalcet was approved for marketing as Orkedia^® that contributes to the achievement of management targets for patients with secondary hyperparathyroidism by taking it once a day and reduces their adverse effects on upper gastrointestinal tracts. This research is an extraordinary drug discovery program where PAM (Positive Allosteric Modulator) of GPCR was succeeded to reach the market.

Lysocin E (1), a macrocyclic natural depsipeptide isolated from Lysobacter sp., exerts potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) via a unique menaquinone (MK)-dependent membrane-disrupting mechanism. Here we report design, construction, and screening of a one-bead-one-compound (OBOC) library consisting of thousands of 1 analogues. To find candidate compounds showing more potent antibacterial activity, we integrated total synthesis of 2401 bead-linked macrocyclic peptides, tandem mass spectrometry-based structure determination, on-bead MK-complexation assay, and in-solution antibacterial assay. Re-synthesis and evaluation of the candidate compounds revealed that 11 new analogues exhibit antibacterial activity superior or comparable to that of 1 and MK-dependent membrane disruption.

Enzymatic functions are often altered during disease onset and progression, and their understanding is indispensable for the development of novel drugs and biomarkers. Authors have been developing the methodologies to globally monitor the enzymatic reactions in living systems to characterize disease-related alteration of enzymatic activities. In this commentary we would like to overview the details of the enzymomics (omics of enzymes) study that authors have been developing.

Japan is anticipated to undergo major changes in the social structure, such as the development of a super-aging society and a decrease in the number of healthcare providers. In the Future Innovation WG, medium- to long-term strategies were examined by backcasting in anticipation of 2040 when IoT, AI, robot technology, etc. were actively incorporated into the fields of health, medical care and nursing care. As a result, the followings are proposed. A “network-type” society which supports each other is ideal, and as an approach to the ideal society, it is important to create new medical and nursing care infrastructures that go beyond the time and space constraints so that anyone can play an important role and it is also important to create of an environment that allows smart access to medical care and nursing care that suits each individual’s condition.