| 研究課題/領域番号 |
22KF0090
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| 補助金の研究課題番号 |
22F22107 (2022)
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| 研究種目 |
特別研究員奨励費
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| 配分区分 | 基金 (2023)
補助金 (2022) |
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| 応募区分 | 外国 |
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| 審査区分 |
小区分47010:薬系化学および創薬科学関連
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| 研究機関 | 東京大学 |
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研究代表者 |
内藤 幹彦 東京大学, 大学院薬学系研究科(薬学部), 特任教授 (00198011)
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| 研究分担者 |
SHIH PO-CHANG 東京大学, 大学院薬学系研究科(薬学部), 外国人特別研究員
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| 研究期間 (年度) |
2023-03-08 – 2024-03-31
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| 研究課題ステータス |
交付 (2023年度)
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| 配分額 *注記 |
2,300千円 (直接経費: 2,300千円)
2023年度: 1,100千円 (直接経費: 1,100千円)
2022年度: 1,200千円 (直接経費: 1,200千円)
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| キーワード | PROTAC / STAT3 / SNIPER / protein degradation |
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| 研究開始時の研究の概要 |
STAT3は多くのがん細胞で活性の亢進が見られる転写因子であり、古くからがん治療の標的タンパク質として注目されているが、これまで有効な阻害剤は開発されていない。本研究では、STAT3を分解する新規SNIPER/PROTAC化合物を開発する事を目的とする。STAT3分解を誘導するSNIPER/PROTACは、新規抗がん剤のリード化合物となることが期待される。
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| 研究実績の概要 |
Proteolysis targeting chimera (PROTAC) is a technology that uses chimeric chemicals to bind to a protein of interest (POI) and an E3 ligase so as to induce POI degradation through the ubiquitin-proteasome system. In this project, we intended to develop novel PROTAC degraders targeting STAT3.
First, we employed sulfonamide derivatives that are believed to bind to the SH2 domain of STAT3 as small molecule-warheads and synthesized PROTACs by conjugating to thalidomide (a cereblon E3 ligase binder) via alkyl linkers. The molecular weights of the resulting PROTACs are approximately 900. Then, the STAT3 degradation activity of these PROTACs were tested along with their parental STAT3 binders in MCF7 and SU-DHL-1 cells. The western blot analysis indicated that PS314 (PROTAC, using PS313 as a warhead) showed a significant activity to reduce STAT3 protein level in both cell lines, while PS312 (PROTAC, using PS311 as a warhead) did not reduce the STAT3 protein level.
We also developed oligonucleotide-warheaded PROTAC molecules against STAT3. A decoy oligonucleotide to which STAT3 binds was conjugated to three different E3 ligands to be LCL-STAT3 decoy, POM-STAT3 decoy and VH-STAT3 decoy. Tested in MCF7 cells, POM-STAT3 decoy was found to be more able to degrade STAT3 than VH-STAT3 decoy, and LCL-STAT3 decoy showed no degradation activity.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We designed various PROTACs/SNIPERs that are categorized into two groups, one with small molecule binders and the other with decoy oligonucleotide to which STAT3 binds. The chimeric molecules were smoothly synthesized and some of the PROTACs showed an activity to reduce STAT3 protein level in cancer cells.
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| 今後の研究の推進方策 |
(1) The degradation activity of PROTACs against STAT3 protein will be convincingly demonstrated by repeated experiments.
(2) The degradation activity of PROTACs will be tested in combination with various inhibitors (E1, E3, proteasome and STAT3), to validate degradation mechanisms.
(3) The active PROTACs will be evaluated for their activity to inhibit growth of cancer cells that are dependent on STAT3, such as lung cancer cells NCI-H2087 and lymphoid cells MOLM16.
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