RESEARCH & PROFESSIONAL EXPERIENCE

After graduating Medical School of Mie University, he entered into Ph.D. course in Mie University, and took Ph.D. by finding the inhibitory mechanism of isoquinolinesulfonamide compounds on protein kinases. Based on the finding, he succeeded to develop specific kinase inhibitors such as H-89, KN62, and CKI-7. One of the isoquinolinesulfonamides, fasudil, was developed as a clinical drug against subarachnoid haemorrhage. When he was a postdoctoral fellow of Marc Montminy’s laboratory in the Salk Institute, he found that transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB (Hagiwara et al. Cell 1992). In addition, he succeeded to identify CBP as the phosphporylated CREB binding protein in collaboration with R. Goodman’s group (Chrivia et al. Nature 1993). When he returned to Japan in 1993, he started his own laboratory in Nagoya University School of Medicine as Assistant Professor. He moved to Tokyo in 1997 as Professor of Medical Research Institute of Tokyo Medical and Dental University and decided to try to decipher splicing code. He moved from Tokyo to Kyoto University in 2010 as Professor and Chairman of Department of Anatomy and Developmental Biology in the Graduate School of Medicine. He is now interested in splicing code of pre-mRNA and developing chemical compounds for new therapeutics of congenital diseases.
The main objective of his research is to develop novel therapeutic methods manipulating transcriptome with small chemicals to cure genetic diseases. To realize the objective, his laboratory has developed original cell-based assay technologies. Initially he succeeded to visualize the activation steps of a transcription factor CREB in living cells by producing a phospho-specific antibody of CREB (Hagiwara et al. MCB 1993). He further developed a fluorescence resonance energy transfer (FRET) method for visualizing phosphorylation of proteins in living cells using a novel fluorescent indicator composed of two green fluorescent protein (GFP) variants joined by the kinase-inducible domain (KID) of CREB (Nagai et al. Nat Biotech 2000). Then, he succeeded to visualize tissue-specific and developmental-stage-specific alternative splicing patterns in living nematode worms, and identified the regulatory factors by genomic mapping of the mutants (Kuroyanagi et al. Nat Methods 2006). To share the newly developed techniques with other researchers of this field, detailed protocols were published (Kuroyanagi et al. Nat Protocols 2010). He further developed the splicing reporter technology, established a dual-color splicing reporter screening system called SPREADD (splicing reporter assay for disease genes with dual-color), applied this to aberrant splicing of IKBKAP exon 20 found in FD patients due to the intronic mutation (IVS20+6T>C), and identified a compound RECTAS that efficiently corrects the mis-splicing of IKBKAP (Yoshida et al. PNAS 2015).
To realize the new therapeutics and rescue patients who suffer incurable diseases, he started his own venture company Kinopharma Co Ltd. in 2005 as an entrepreneur. In cooperation with Kinopharma, he has developed an anti-virus drug FIT039 targeting host factors required for virus proliferation. FIT039 specifically inhibits CDK9 and suppresses viral transcription of a broad spectrum of DNA viruses including HCMV, HAdV, HBV and HPV without significant adverse effect on mammalian cells (Yamamoto et al. J Clin Invest. 2014, Ajiro et al. Clin Cancer Res. 2018). Thus, the phase1/2a clinical trial of FIT039 is under way in Kyoto University Hospital for the patients of skin warts caused by Human papilloma virus. The clinical trial for cervical cancer of uterus with FIT039 will also start soon.