Mochida Pharmaceutical is conducting drug discovery research focusing on siRNA drugs. siRNAs can act on targets that small molecules and antibodies cannot, and are expected to create drugs for diseases that were previously impossible to treat. Platform drug discovery has the advantages of faster compound creation and high clinical predictability. Reflecting these advantages, there has been a series of successful launches of siRNA drugs in recent years. At a time when few companies have yet to engage in full-fledged siRNA drug discovery, we will do our utmost to promote siRNA drug discovery projects and technological development, and expand our lead in the field. Our goal is to become a “leading company in siRNA drug discovery” in the future.

Taiwan’s new drug development has progressed significantly due to advances in biotechnology, policy support, and industry-academia collaboration. Key areas include antibody-drug conjugates, AI-driven drug design, novel chemical entities, and innovative drug formulations. Government initiatives like the precision health strategy and 505(b)(2) regulatory pathway have attracted investment and accelerated clinical development. Successes in rare diseases, oncology, and long-acting formulations showcase Taiwan’s growing global competitiveness. Looking forward, strengthening international collaboration, intellectual property strategy, and talent cultivation will be essential for sustaining momentum and advancing Taiwan’s pharmaceutical industry to the next level. Pharmacy education in Japan and Taiwan each has its own strengths-Japan emphasizes practical experience and attention to detail, while Taiwan focuses on flexibility and interdisciplinary learning. Through mutual exchange, students can broaden their global perspective and humanistic qualities. In the future, combining the strengths of both systems may cultivate outstanding pharmacy professionals with solid theoretical foundations and practical skills.

Boron neutron capture therapy (BNCT) is a cancer treatment that selectively destroys tumor cells by irradiating boron compounds, which are preferentially accumulated in cancer cells, with thermal neutrons. In this study, we developed a novel boron carrier, PBC-IP, which targets folate receptor α (FRα) and possesses the ability to bind serum albumin. PBC-IP is water-soluble and exhibits low cytotoxicity. In glioma cell lines, PBC-IP showed 10- to 20-fold higher intracellular accumulation compared to 4-borono-L-phenylaranin (L-BPA). Furthermore, in orthotopic glioma rat models, convection-enhanced delivery (CED) of PBC-IP achieved remarkably high tumor selectivity (T/N and T/B ratios) and excellent therapeutic efficacy. Notably, co-administration with L-BPA resulted in a synergistic therapeutic effect, suggesting the potential of PBC-IP as a promising agent in next-generation BNCT strategies.

BRD4 is a key protein in epigenetics research, especially in cancer and inflammation. Many inhibitors are under clinical investigation, particularly in cancer. BRD4 contains two bromodomains, BD1 and BD2, and selective inhibitors have been extensively studied to investigate their biological functions. Most BD1-selective inhibitors lack sufficient selectivity, and even the most highly selective compound reported to date has poor oral bioavailability, resulting in inadequate in vivo functional validation. In this study, we analyzed the amino acid differences between BD1 and BD2 using X-ray crystallography. Through rational compound design, we combined multiple interactions to create a BD1 inhibitor with potent BD1 inhibition, the highest selectivity for BD2 inhibition in the world, and oral bioavailability. This new BD1 inhibitor addresses the limitations of previous compounds and enables effective in vivo functional validation.

Dopamine D3 receptor antagonists are expected to be highly effective in treating symptoms of attention-deficit/hyperactivity disorder (ADHD) without inducing addiction. However, achieving selective targeting is challenging, as D3 receptors share a high degree of amino acid homology with D2 receptors and aminergic G protein-coupled receptors (GPCRs), increasing the likelihood of off-target effects. Lead optimization starting with compound 1 resulted in the identification of compound 10, which exhibited a high binding affinity for D3 and high selectivity against the D2 receptor. We successfully conducted a structural analysis of the D3 receptor in complex with compound 10, ultimately identifying factors for D2/D3 selectivity. Further optimization yielded compound 11, which exhibited excellent in vitro potency/selectivity and a suitable ADMET profile. Moreover, this compound selectively occupied the D3 receptor and demonstrated efficacy in reducing impulsivity and improving cognitive function in rats. These results suggest that compound 11 is a promising candidate for ADHD treatment.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. After the promising results from clinical trials of FG-2216 (FibroGen’s HIF-PHD inhibitor), many pharmaceutical companies recognized the potential of HIF-PHD inhibitor and started developing their own HIF-PHD inhibitors. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with the compound. By optimizing the pyrimidine substituents, we discovered compound 4, which improves the effectiveness of erythropoietin (EPO) release from Hep3B cells. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vivo activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its oral administration for 4 consecutive days.

Enhancer of zeste homolog (EZH), a catalytic subunit of polycomb repressive complex 2 (PRC2), is an enzyme that methylates the lysine 27 on histone H3 (H3K27), and there are two homologs, EZH1 and EZH2. EZH plays an important role in the development and progression of cancer, and is therefore considered a promising target for antitumor drugs. We have created a group of orally available compounds with a characteristic acetal structure that simultaneously inhibit both EZH1 and EZH2. These compounds showed strong antitumor activity, mainly in blood cancer cell lines, by strongly inhibiting trimethylation of H3K27 (H3K27me3). Valemetostat (DS-3201), discovered from this group of compounds, was approved in Japan in 2022 as the world’s first EZH1/2 dual inhibitor.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to threaten public health. Although several vaccines and neutralizing antibodies against SARS-CoV-2 variants exist, the efficacy of these treatments against new SARS-CoV-2 variants is limited because many SARS-CoV-2 variants have mutations mainly in the spike protein compared with the ancestral SARS-CoV-2. In this study, we identified S-880008, a lipid-modified macrocyclic peptide, through mRNA display screening with SARS-CoV-2 spike proteins and chemical modification. In a cell-based assay, S-880008 has a broad-spectrum anti-SARS-CoV-2 activity, including Omicron variants. Furthermore, the mode of action analysis suggests that S-880008 does not inhibit the viral attachment to the host cell, but rather inhibits the process of viral fusion with the host cell membrane after viral attachment.

BACE1 inhibition is an attractive approach for maintenance therapy after anti-Aβ antibody treatment in Alzheimer’s disease. Unfortunately, clinical BACE1 inhibitors, such as atabecestat, exhibited hepatotoxicity, cognitive impairment, or cardiotoxicity in clinical trials, thus preventing their use for maintenance therapy. Hence, we focused our efforts on finding BACE1 inhibitors with mitigated adverse effects. As hepatotoxicity could be caused by reactive metabolites derived from the thiazine ring, it was replaced with oxazine. To avoid cognitive impairment, we aimed at improving selectivity over BACE2. These efforts led to the design of THP-fused oxazine derivatives that can recognize the difference in the flap regions as well as achieve a minimal energy difference between an active and the most stable conformation. The newly discovered S-872881 exhibits >100-fold binding selectivity, significantly inhibits Aβ production in dogs without BACE2 inhibition, and displays a sufficient safety margin in vivo.