ONO Pharmaceutical has taken a new step toward further challenges beyond the major milestone of the 300th anniversary, since its establishment in 1717 as an apothecary by Ichibei Fushimiya in Doshomachi, Osaka. To be a “Global Specialty Pharma”, who can continuously develop and launch new innovative drugs that deliver true benefit to patients in global market, Ono has been evolving our drug discovery style, e.g. focusing on the prioritized disease areas, adopting several new modalities, establishment of ONO Pharma foundation and Ono Venture Investment in order to accelerate innovative collaboration. Here we describe drug discovery activities at ONO to date and recent changes surrounding medicinal chemists.

At the 2018 Russia World Cup, 15 of the 23 registered members of the Japanese national team were selected from European clubs. Considering that there were just 4 people who were selected from European clubs at the 2010 South Africa World Cup, this is a phenomenal breakthrough. On the other hand, in Japan, which has a lot of talented chemists, it has been common to work at an overseas research institution since 19th century. Some of you may be going to study abroad. I think there are various purposes, but what is important is to raise the market value of oneself and step up as in the soccer world, and by extension, to raise the market value of Japanese society itself.

Lead exploration unit, the University of Tokyo (DDI-LEU), was established in 2016 by Japan Agency for Medical Research and Development (AMED), as an internal organization of Drug Discovery Initiative (DDI), with the aim of enhancing the probability of innovative drug creation from academia. In DDI-LEU, hit-to-lead synthesis support will be conducted mainly by the active researchers from pharmaceutical companies, taking into account of ADME and physicochemical property evaluation, both of which were difficult to implement in the past in the academia for more than 4 years, under the BINDS program (Basis for Supporting Innovative Drug Discovery and Life Science Research). In the near future, to further improve the accuracy of support-efficiency, DDI-LE would like to develop toward the realization of advanced support.

In a recent drug discovery diversification of modality is progressing represented by antibody drugs, nucleic acid drugs and gene therapies. This seems to be attributed to the progress of platform technologies for each modality and high demand for unmet medical needs. In this environment small molecule drugs are used dominantly for the treatment of patients and still occupy large portion of clinical pipeline in each drug discovery company. Recently several new technologies/approaches are discovered in small molecule drug discovery world and this enable us to create new type of drugs which could not be realized by ordinal approaches. In this article the potential of small molecule drug discovery and representative new technologies/approaches are introduced.

Transthyretin (TTR) amyloidosis is a disease that causes amyloid deposits in the heart, kidneys, gastrointestinal tract, and eyes. Small molecule drug discovery is being carried out with a strategy of stabilizing the TTR structure and inhibiting amyloid fibril formation. Tafamidis, AG10, diflunisal and tolcapone are known as small molecule drugs. The potency and efficacy of these small molecule stabilizers were found to correlate with the binding enthalpy with TTR. X-ray crystallography revealed that AG10-TTR mutant complex recreated the structure of the T119M-TTR mutant. NMR analysis showed that the difference in main chain chemical shift between wild-type TTR and mutant TTR resulted in significant structural differences between them.

Progress in RNA research following the decoding of human genomes has revealed that RNA plays an important role in intracellular signal transduction and gene regulation and is involved in many diseases. RNA is expected to provide new opportunities for small molecule drug discovery that have targeted druggable proteins. In August 2020, SMN2-directed RNA splicing modifier, risdiplam was approved by the FDA as a small molecule drug for spinal muscular atrophy. This spurs active discussion on the possibility of small molecule drug discovery targeting RNA. In this review, I will summarize the history of RNA-targeting small molecules and the discovery of risdiplam. I will also describe the prospects of small molecule drug discovery targeting RNA.

Blocking the immune checkpoint receptor (PD-1) or its ligand (PD-L1) with antibodies has proven to be an effective treatment for multiple cancer types, and the success of this cancer immunotherapy has led to a paradigm shift in cancer treatment. The drug discovery aimed at inhibiting the target proteins, whose pharmacological outcomes are proven to be effective with the antibody, with inexpensive and orally available small-molecule drugs has a high hurdle to overcome, but are of great significance. In this article, we will introduce various approaches to drug discovery that are unique to small molecules, which demonstrate a different mechanism of action from those of antibodies and have similar drug effects to those of antibodies.

Chemical knockdown, degradation of specific proteins by small organic compounds, has attracted a great deal of attention in recent drug discovery efforts as a new modality. The “protein degrader” can disrupt the function of a protein by inducing selective proteolysis of the target protein itself, which is a totally different molecular mechanism than those of existing enzyme inhibitors and receptor antagonists. In addition, lenalidomide and fulvestrant, both of which are anticancer agents already on the market and clinically used, also belong to the class of protein degrader, and novel pharmacological effects beyond simple outcomes of conventional enzyme inhibition and receptor antagonism have been indicated. Therefore, it is expected that this new modality might greatly increase the variety of druggable target proteins in drug discovery and development. Here, we outline the technological progress, challenges, and prospects of the protein degraders, which are rapidly being developed in recent years.

In order to enable innovative drug discovery, the development of next-generation medical modality is strongly desired. We have organized the “LiHub Next Generation Medical Modality Group” and aim to create next generation medical modality by integrating diverse knowledge, technology, and human resources. In this report, I’m going to introduce our activities, purpose, and achievements so far.