2022 Fiscal Year Final Research Report
Establishment of a novel drug discovery platform for adult T-cell leukemia/lymphoma using PROTAC technology
| Project/Area Number |
20K08736
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kagoshima University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
石塚 賢治 鹿児島大学, 医歯学域医学系, 教授 (10441742)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 成人T細胞白血病リンパ腫 / CARD11 / PROTAC |
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| Outline of Final Research Achievements |
We aimed to develop a novel therapeutic agent for adult T-cell leukemia-lymphoma (ATL) using a targeted proteolysis-inducing compound (PROTAC), targeting CARD11, since many cases of ATL show gain-of-function mutations in CARD11. Since crystals of the full length of CARD11 could not be obtained, partial crystallization of the SH3-GUK domain of the C terminal was investigated. In addition, crystallization of only the SH3 domain was performed in parallel. Crystallization under various conditions was attempted, but it was found that the SH3-GUK domain is truncated at a specific sequence between SH3 and GUK. We are aiming to remove the cleavage site by introducing mutations.
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| Free Research Field |
血液内科学
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| Academic Significance and Societal Importance of the Research Achievements |
PROTAC技術を用いてATLへの新規治療薬の開発を目指した初の研究である。標的蛋白として多数例で機能獲得型変異を有しているCARD11を標的とした。これまでCARD11の蛋白構造は解かれておらず、その解析を試みた。創薬等先端技術支援基盤プラットフォーム（BINDS）の支援を受けることもできた。適切な支援のもとに検討されたため、X線結晶構造解析でのCARD11の構造解析が困難であることが明らかとなった。Cryo電顕などを用いた取り組みも必要である可能性が示唆された。
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