| Project/Area Number |
12219205
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | RIKEN (2002-2004)
The University of Tokyo (2000-2001) |
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Principal Investigator |
YOSHIDA Minoru RIKEN, Discovery Research Institute, Chemical Genetics Laboratory, CHIEF SCIENTIST, 中央研究所 吉田化学遺伝学研究室, 主任研究員 (80191617)
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| Co-Investigator(Kenkyū-buntansha) |
堀之内 末治 東京大学, 大学院・農学生命科学研究科, 教授 (80143410)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥129,700,000 (Direct Cost: ¥129,700,000)
Fiscal Year 2004: ¥25,000,000 (Direct Cost: ¥25,000,000)
Fiscal Year 2003: ¥29,000,000 (Direct Cost: ¥29,000,000)
Fiscal Year 2002: ¥25,500,000 (Direct Cost: ¥25,500,000)
Fiscal Year 2001: ¥26,200,000 (Direct Cost: ¥26,200,000)
Fiscal Year 2000: ¥24,000,000 (Direct Cost: ¥24,000,000)
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| Keywords | ACETYLATION / HDAC / MICROTUBULE / CYCLIC TETRAPEPTIDES / DRUG DESIGN / THIOL / FK228 / SCOP / プロドラッグ / エンドサイトーシス / トラポキシン / ヒストンデアセチラーゼ / 酸化還元 / トリコスタチン / チューブリン / ヒストン / グルタチオン / 細胞周期 / ラディシコール / ヒストンアセチル化 / 転写制御 / クロマチン |
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| Research Abstract |
We have identified histone deacetylases (HDAC) as the molecular target of trichostatin A (TSA) and trapoxin (TPX), microbial metabolites that inhibit mammalian cell cycle. Recently, we have shown that FK228, a potent anti-cancer agent under the phase II clinical trials in the US, also specifically inhibits HDAC. Since accumulating evidence suggests that HDAC is a novel molecular target for anti-cancer drugs, we developed new types of HDAC inhibitors in this project The X-ray crystallographic studies suggested that TSA inhibits HDAC by chelating the active-site zinc with its hydroxamic acid group, while TPX covalently modifies an active site residue via its epoxiketone moiety. We synthesized a hybrid inhibitor by coupling the cyclic tetrapeptide of TPX with the hydroxamic acid of TSA, named CHAP CHAP was shown to be a potent HDAC inhibitor. In contrast to TSA or TPX, CHAP was highly stable in serum and a derivative (CHAP31) showed potent antitumor activity in the xenograft models. FK228 has an intramolecular disulfide. We showed that FK228 is a natural prodrug, which can be converted to the reduced form with a thiol group interacting with the active-site zinc by cellular reducing activity. We therefore designed a new type of inhibitors by introducing the thiol group into the TPX-like cyclic tetrapeptide inhibitors named SCOP. SCOP was normally oxidized and inactivated but became active when it is reduced in cells. The HDAC family includes more than ten species of enzymes. TSA inhibited almost all the enzymes but TPX failed to inhibit HDAC6. By using the differential sensitivity, we identified that HDAC6 is the tubulin deacetylase. Since each member of HDAC family may have each distinct function, it is important to develop subtype-specific inhibitors. During the course of screening forth subtype-specific inhibitors, we found a SCOP derivative that specifically inhibits HDAC4.
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