水上 民夫（みずかみ・たみお）
Tamio Mizukami
職位：研究部長、教授
学位：農学博士（京都大学）
●京都大学大学院農学研究科修士課程修了
●米国NIH客員研究員、協和発酵工業㈱東京研究所主任研究員等を歴任
専門分野
抗がん剤創薬、遺伝子科学
研究テーマ
抗がん剤創薬を研究主題とし、創薬標的遺伝子や創薬リード化合物の探索技術の開発、またがん遺伝子産物のような、細胞がん化の原因分子をターゲットとする分子標的抗がん剤の創薬を展開しています。
（1）創薬システムの新規基盤技術開発
創薬ターゲットの探索や機能検証、創薬リード化合物の探索や最適化プロセスの新規基盤技術の開発を行っています。特に、"ヒト化酵母"を用いるケミカルゲノミクス（化合物を利用する網羅的な遺伝子機能解析手法）による創薬ターゲット・リード化合物の探索・同定の技術開発に取り組んでおり、抗がん剤創薬の標的として期待される新規機能タンパク質やその阻害剤の同定に成功しています。
（2）分子標的抗がん剤の創薬
細胞がん化の原因分子をターゲットとする新世代の分子標的抗がん剤の開発を目標としています。特に、エピジェネティクスやがん化特異的パスウェイを標的とする抗がん剤の開発を行っています。中でもエピジェネティクス分野の新世代の創薬標的として期待されるヒストン脱メチル化酵素の阻害剤開発に最近は注力しています。また同定したリード化合物を臨床試験に効率的に到達させるために、バイオマーカーの活用など、POC（コンセプト証明）重視の最先端創薬システムを実践しています。
Topics of research
Research and development of anticancer drugs targeting causative molecules of tumorigenesis have been actively promoted since discovery of human oncogenes in 1980s. The innovative molecular-targeted drugs such as Trastuzumab and Imatinib are typical fruits of the efforts for the past decade. Methodology developments and achievements of genomics research including completion of the human genome sequencing in 2003 are drastically changing the drug discovery system for cancer. Cancer medicine now enters an era of personalized medicine in which characteristics of a cancer and individual constitution of a patient are reflected in the therapeutic treatment. Utilization of biomarkers is an important issue for this personalized medicine. It is strongly pointed out that the action of a drug on its target should be validated at the early phase of clinical trials in view of the "proof of concept (POC)" in order to increase the success rate of drug discovery. In accordance with the recent oncology R&D trend, Mizukami's laboratory is aiming to explore fundamental technologies for drug discovery system, to discover novel cancer-causing genes, and to develop a new generation of molecular-targeted anticancer agents.
Topic-1: Comprehensive Screening of Human Genes with Inhibitory Effects on Yeast Growth and Validation of a Yeast Cell-Based System for Screening Chemicals. The "humanized yeast project", in which comprehensive screening of human cDNAs that inhibit yeast growth has been designed. 10,302 human cDNAs (~50% of the total cDNAs) was expressed in a budding yeast (Saccharomyces cerevisiae) and found that approximately 5.6% of the cDNAs, including those for protein kinases, interfered with the yeast growth. Known inhibitors for protein kinases were examined for whether they reversed the c-Yes tyrosine kinase-induced inhibition of the yeast growth. Among 85 inhibitors tested, six compounds (PP2, PP1, SU6656, purvalanol, radicicol and geldanamycin) reversed the inhibition, indicating a high specificity sufficient for validating this screening system (Sekigawa M. et. al, J Biomol Screen. In press. (2010)).
Topic-2: Identification of cell-active lysine specific demethylase 1-selective inhibitors. Lysine specific demethylase 1(LSD1), the first histone demethylase discovered, removes the methyl groups from mono- and dimethylated Lys4 of histone H3. LSD1 is highly expressed in prostate and breast cancer and neuroblastoma, and could be a next generation drug discovery target of cancer epigenetics. Based on the crystal data of LSD1 and its nonselective inhibitor, tranylcypromine, small molecules were newly designed. The inhibitors showed more than 10 times stronger inhibitory activity than tranylcypromine and their LSD 1 selectivity was 400-11,000 times greater than that of tranylcypromine. These inhibitors are anticancer-agents candidate as well as useful tools for studying the biological roles of LSD1 (Ueda R. et. al, J. Am. Chem. Soc. 131, 17536-17537 (2009)).
主な業績論文等
- Ueda R, Suzuki T, Mino K, Tsumoto H, Nakagawa H, Hasegawa M, Sasaki R, Mizukami T, Miyata N: Identification of cell-active lysine specific demethylase 1-selective inhibitors. J. Am. Chem. Soc. 131, 17536-17537 (2009)
- Nakai R, Ishida H, Asai A, Ogawa H, Yamamoto Y, Kawasaki K, Akinaga S, Mizukami T, Yamashita Y: Novel Telomerase Inhibitors Identified by a Forward Chemical Genetics Approach Using a Yeast Strain with Shortened Telomere Length. Chem Biol. 13, 183-190（2006）
- Takahashi I, Miyaji H, Yoshida T, Sato S, Mizukami T: Selective inhibition of IL-2 gene expression by trichostatin A, a potent inhibitor of mammalian histone deacetylase. J. Antibiot. 49, 453-457 (1996)
- Mizukami T, Fuerst TR, Berger EA, Moss B : Binding region for human immunodeficiency virus（HIV）and epitopes for HIV-blocking monoclonal antibodies of the CD4 molecule defined by site-directed mutagenesis. Proc. Natl. Acad. Sci. U S A 85, 9273-9277（1988）
- Chaudhary VK, Mizukami T, Fuerst TR, FitzGerald DJ, Moss B, Pastan I, Berger EA Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas exotoxin hybrid protein. Nature 335,369-372（1988）
