Innovation Center of NanoMedicine (iCONM), KAWASAKI INSTITUTE OF INDUSTRIAL PROMOTION started its operation in Kawasaki Tonomachi area, where the medical research institutions and industries have been developing, namely KING SKYFRONT, as a core research center in April, 2015. In iCONM, industry-overnment-academia gather under the one roof and conduct research on smart nanomachines which are the size of virus (-50nm) that autonomously circulate the microenvironments in the body, work only at the targeted site and accurately respond to the biological information. We aim to realize “in-body hospitals” that patrol around the body 24 hours a day and provides “necessary diagnosis and treatment inside the required parts of the body at the precise time” with this nanomachines.

Small-molecule approach can be complementary to genetic approaches for exploring biology and beyond. The Institute of Transformative Bio-Molecules (ITbM) at Nagoya University aims at developing game-changing molecules and molecular technology for plant biology, chronobiology, and live imaging. Through our intensive interdisciplinary ollaboration, a number of lead compounds were rapidly discovered at ITbM. The overview of ITbM and our exciting on-going collaborative projects merging synthetic chemistry, plant biology, animal biology, computational chemistry, and live imaging are described.

The author had an opportunity to be deeply involved in the discovery research of unprecedented boron-containing drugs in a biotech start-up founded in Silicon Valley for more than 10 years. During that period, two products have reached FDA approval and launch. It was very intriguing to observe the progress of the research and development as well as the growth of the company as an insider. The author also obtained precious experiences and learnings in a different environment than that of Japan. What was especially important was the project management for the success of start-ups. The author would like to describe the above contents as a case study of US biotech start-up.

Trametinib is a highly potent, highly selective allosteric inhibitor of MEK1 and MEK2. This compound was licensed to GSK from JT in 2006, and then it was approved in the U.S. as a first-in-class MEK inhibitor in 2013, and was also approved in Japan in 2016. Although a drug discovery research of trametinib has already been published in MEDCHEM NEWS Vol.27 No.3, we would like to supplement it from a chemistry perspective since we have received the Breakthrough Award, Division of Medicinal Chemistry, PSJ.

Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. In our research, we found a oxadiazinone derivative through HTS using AMPA induced neuronal cell death assay and in vitro [Ca²⁺] influx assay. From further investigation, we achieved a novel 1,3,5-triarylpyridone via 2,4,6-triarylpyridazinone. Optimization of the pyridone scaffold led to the discovery of perampanel as an orally active noncompetitive antagonist of AMPA-type ionotropic glutamate receptors for partial-onset seizures associated with epilepsy.

In human genome, 650,000 protein-protein interactions (PPIs) are predicted to regulate biological processes. Specific inhibitors regulating aberrant PPIs are expected to be therapeutics. In spite of this clear goal, generation of de novo PPI inhibitors are still challenging in drug discovery. Antibodies with inhibitory activities against aberrant PPIs have been developed as antibody drugs, but the drug developments are still limited for extracellular PPI targets, because antibody lacks cell-penetrating activity and that leads no accessibility to intracellular PPIs. Here we have developed a cyclized helix-loop-helix (cHLH) peptide “microantibody” as a molecular scaffold for generating PPI inhibitors against extracellular and intracellular PPIs. Here we describe microantibodies generated by directed evolution technologies or by protein epitope grafting based on the structural information of target proteins. Then we report how we desinged microantibody cHLHp53-R inhibiting intracellular p53-HDM2 interaction.

Huntington’s disease is a neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of this toxic aggregation-prone protein is expected to be an effective therapeutic approach. We designed small hybrid molecules composed of a ligand for ubiquitin ligase and probes for aggregates, anticipating that these molecules would bring the ubiquitin ligase into close proximity to mHtt, leading to degradation of mHtt by the ubiquitin-proteasome system. The synthesized small molecules reduced mHtt levels in living cells. Analysis of the mode of action revealed that these small molecules induced complex formation between Htt aggregates and the ubiquitin ligase, and this led to proteasomal degradation of mHtt. Thus, we show that hijacking ubiquitin ligase induced by using small hybrid molecules could be effective therapeutic approach for neurodegenerative diseases.

DNA-encoded library (DEL) has attracted much attention as a promising approach for efficient ligand generation. Taking advantage of unique characteristics of DNA, DEL has realized drug discovery using a small molecule library with an unprecedented diversity. This review article summarizes the construction methods for DEL with a particular focus on chemical properties of DNA.