Based on the frontier basic research, Osaka University has an important mission to return the research results to society as drug discovery. Drug Discovery Science Division, the Institute for Open and Transdisciplinary Research Initiatives is the command center for drug discovery research at Osaka University, which promotes cross-divisional collaborative research. Center for Supporting Drug Discovery and Life Science Research at Graduate School of Pharmaceutical Sciences, which is composed of Compound Library Screening Center and Drug Innovation Center consisting of Lead Exploration Units and Pharmacokinetics Safety Test Units supports a leading-edge technology for drug discovery in cooperation with AMED BINDS (Basis for Supporting Innovative Drug Discovery and Life Science Research) program to promote academia drug discovery in Japan.

I had a great opportunity to research abroad in the Houston Methodist Research Institute (HMRI) for 1.5 years. HMRI is located in the Texas Medical Center (TMC) which is the largest medical city in the world. Professor Ennio Tasciotti in HMRI is proceeding with the Biomimetic Nanoparticles research projects for clinical application. While I dedicated to this project, I learned the effective team building strategies as well as the research and discussion skills with the multinational members having their own cultures and working styles. In addition, HMRI and TMC gave me a lot of chances to attend the interesting lectures and conferences to broaden my knowledge from basic to clinical sciences. The amazing encounters with researchers and medical doctors in TMC made my Houston life exciting and fulfilling. This article describes my experiences in HMRI and TMC.

Renin is the rate-limiting and first step of the renin-angiotensin system, and direct renin inhibitors (DRIs) show potent hypotensive effect without increasing plasma renin activity, unlike ARBs and ACE inhibitors. Furthermore, clinical studies have demonstrated the potential of DRIs for renal and cardiac protection. Although DRIs have been searched for several decades, most of them have poor pharmacokinetics and oral absorption because of peptide-like structures or nonpeptide-like structures with molecular weight close to 700. Aliskiren, which was approved as the first orally bioavailable DRI in 2007, also has low bioavailability (2~3%). We discovered SPH3127, which has a nonpeptide-like structure and molecular weight less than 500. It has higher bioavailability and more potent hypotensive effect in non-clinical models than Aliskiren, and is currently under Phase II clinical trial. In this report, we show the details of optimization to improve renin inhibitory activity and pharmacokinetics without significant increase in molecular weight.

Levodopa known as prodrug of dopamine is one of the most powerful agent for treating Parkinson’s disease (PD). However, pharmacokinetic (PK) profile of Levodopa has issue of its metabolism in peripheral caused short duration. To address this PK issue, we inspired to make Levodopa prodrug to improve Levodopa duration in plasma. We synthesized more than 700 compounds and evaluated dog PK study to find ONO-2160 that had good PK profile in animals. ONO-2160 and dopa decarboxylase inhibitor (DCI) combination showed long duration in both dogs and rodents. ONO-2160 and DCI combination also showed good PK profiles in healthy volunteers and PD patients in Phase I study.

The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 1 having a 4-(4-(quinolin-3-yl)-1H-indol-1-yl) benzamide structure. TAS-116 (9) is a selective inhibitor of HSP90α and HSP90β among the HSP90 family proteins and exhibits oral availability in mice. The X-ray co-crystal structure of TAS-116 analog 8 demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of TAS-116 demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant loss of body weight. In this study, we report on the process of compound optimization from the initial hit compound 1 to the discovery of TAS-116, X-ray co-crystal structure analysis of compound 8, and the results of in vivo efficacy study.

Antibody-drug conjugates (ADCs) have become a major class of cancer biopharmaceuticals and traditional ADCs have a stochastic distribution of cytotoxic drugs linked across several different sites of the antibody. The heterogeneous nature of resulting stochastic ADCs can cause diminished efficacy and increased toxicity, thus limiting the corresponding therapeutic index. To improve on traditional ADC technology, we developed and report here a novel chemical conjugation platform termed “AJICAP™” for the site-specific modification of native antibodies through the use of a class of IgG Fc-affinity reagents. Site-specific installation of thiol functional groups to well-defined lysine residues in IgGs followed by conjugation to these newly installed thiols with cytotoxic payloads was efficiently conducted to generate AJICAP™-ADCs. Several results described that AJICAP™-ADCs expand the therapeutic window compare to random conjugated ADCs. AJICAP™ technology is a powerful platform to enable next-generation ADCs through the reduction of heterogeneity and enhanced of therapeutic index.

A novel method for electrochemical C(sp³)-H fluorination has been developed under an academia-industry collaborative research. Using Selectfluor and a nitrate salt, a wide range of aliphatic C-H bonds can be converted to C-F bonds in a single step without the requirement of existing functional groups. Here we describe the detail of our collaborative research, including protocol optimization, substrate scope and limitations, and its application to Eisai in-house compounds, especially to tropane compounds. The impact of fluorination on drug-likeness properties was also assessed, and significant improvements on P-gp liability and hERG/Nav 1.5 inhibitory were observed.

The evaluation of specificity between a candidate drug and its target molecule is an important indicator in molecular-targeted drug discovery. The physicochemical analysis technique is a powerful tool to understand this specificity. The strength of physicochemical analysis is the hit validation and lead generation of compounds selected by screening. Since each of these techniques can yield data based on unique principles, a combination of these techniques to evaluate pleiotropically allows us to adapt to other diverse targets, such as membrane proteins or protein-protein interactions. In this article, we review the recent progresses on physicochemical techniques for small molecule drug discovery, including our recent works.