研究概要

私たちは、化学的アプローチ（ケモテクノロジー）を駆使して、ユビキチン修飾系を理解し、操作する新たな方法論を開拓しようとしており、本研究はその基盤となるツール開発を目的とするものです。その中心となる技術は、UbTACsと名付けた新たなユビキチン化誘導キメラ分子です。SNIPERあるいはPROTACsと呼ばれるキメラ化合物は、ユビキチンリガーゼをハイジャックすることで本来の標的分子以外の基質タンパク質（ネオ基質）をユビキチン化して、分解誘導します。この技術を発展させて、単にネオ基質のノックダウンだけでなく、エンドサイトーシス、シグナル伝達、オートファジーなどを誘導できる新しいユビキチン化誘導キメラ分子の創出を目指します。これらを実現するために、新規なE3リガンドやネオ基質のリガンド化合物の探索やそれをキメラ化する技術が必要です。そのために、私たちが開発した迅速な多検体スクリーニングを可能とする化合物アレイ技術を用いて、新規なE3リガンドやネオ基質のリガンド化合物を探索していきます。化合物アレイは、理研天然化合物バンク（NPDepo）の約2万2千のライブラリー化合物をスライドガラス上に光親和型固定化法により固定化してあり、タンパク質との物理的相互作用を指標に結合する化合物を見いだすことが出来ます。化合物アレイにより見出したリガンド候補化合物は、2次元SPRまたはビアコアを用いて結合親和性の解析を行い、化合物の絞り込みを行っていきます。見出したリガンド化合物は、類縁化合物を用いた構造活性相関研究により、キメラ化するための官能基の同定を行い、UbTACsの開発へ繋げていきます。

研究概要を示す模式図

本領域での研究成果

1. Suvarna K, Honda K, Muroi M, Kondoh Y, Osada H, *Watanabe N.
   A small-molecule ligand of valosin-containing protein/p97 inhibits cancer cell-accelerated fibroblast migration.
   J. Biol. Chem. 294, 2988-2996 (2019)
   PMID: 30610116
2. Shu K, Iwamoto N, Honda K, Kondoh Y, Hirano H, Osada H, Ohno H, Fujii N, Oishi S.
   Development of mirror-image screening systems for XIAP BIR3 domain inhibitors.
   Bioconjug. Chem. 30, 1395-1404 (2019)
   PMID: 30888797
3. Murashima A, Shinjo K, Katsushima K, Onuki T, Kondoh Y, Osada H, Kagaya N, Shin-Ya K, Kimura H, Yoshida M, Murakami S, Kondo Y.
   Identification of a chemical modulator of EZH2-mediated silencing by cell-based high-throughput screening assay.
   J. Biochem. 166, 41-50 (2019)
   PMID: 30690451
4. Takase S, Kurokawa R, Kondoh Y, Honda K, Suzuki T, Kawahara T, Ikeda H, Dohmae N, Osada H, Shin-Ya K, Kushiro T, *Yoshida M, *Matsumoto K.
   Mechanism of action of prethioviridamide, an anticancer ribosomally synthesized and post-translationally modified peptide with a polythioamide structure.
   ACS Chem. Biol. 14, 1819-1828 (2019)
   PMID: 31365229
5. Yoshida K, Kondoh Y, Iwahashi F, Nakano T, Honda K, Nagano E, Osada H.
   Abscisic acid derivatives with different alkyl chain lengths activate distinct abscisic acid receptor subfamilies.
   ACS Chem. Biol. 14, 1964-1971 (2019)
   PMID: 31497942
6. Suvarna K, Honda K, Muroi M, Kondoh Y, Osada H, *Watanabe N.
   Measurement of ATPase activity of valosin-containing protein/p97.
   Bio-protocol 10, e3516 (2020)
7. Suvarna K, Honda K, Muroi M, Kondoh Y, *Watanabe N, *Osada H.
   Identification of target protein for bio-active small molecule using photo-cross linked beads and MALDI-TOF mass spectrometry.
   Bio-protocol 10, e3517 (2020)
8. Sako K, Futamura Y, Shimizu T, Matsui A, Hirano H, Kondoh Y, Muroi M, Aono H, Tanaka M, Honda K, Shimizu K, Kawatani M, Nakano T, Osada H, Noguchi K, *Seki M.
   Inhibition of mitochondrial complex I by the novel compound FSL0260 enhances high salinity-stress tolerance in Arabidopsis thaliana.
   Sci. Rep. 10, 8691 (2020)
   PMID: 32457324
9. Ikeda H, Muroi M, Kondoh Y, Ishikawa S, Kakeya H, Osada H, *Imoto M.
   Miclxin, a novel MIC60 inhibitor, induces apoptosis via mitochondrial stress in β-catenin mutant tumor cells.
   ACS Chem. Biol. 15, 2195-2204 (2020)
   PMID: 32584541
10. Kawamura T, Futamura Y, Shang E, Muroi M, Janning P, Ueno M, Wilke J, Takeda S, Kondoh Y, Ziegler S, Watanabe N, Waldmann H, *Osada H.
    Discovery of small-molecule modulator of heterotrimeric Gi-protein by integrated phenotypic profiling and chemical proteomics.
    Biosci. Biotechnol. Biochem. 84, 2484-2490 (2020)
    PMID: 32867616
11. Fujita K, Kondoh Y, Honda K, Haga Y, Osada H, Matsumura C, *Inui H.
    Pesticide treatment reduces hydrophobic pollutant contamination in Cucurbita pepo through competitive binding to major latex-like proteins.
    Environ. Pollut. 266, 115179 (2020)
    PMID: 32717636
12. Sophonnithiprasert T, Aruksakunwong O, Tashiro E, Kondoh Y, Muroi M, Osada H, Imoto M, Watanapokasin R.
    Interaction between goniothalamin and peroxisomal multifunctional enzyme type 2 triggering endoplasmic reticulum stress.
    Heliyon 6, e05200 (2020)
    PMID: 33102840
13. Nagashima S, Maruyama J, Honda K, Kondoh Y, Osada H, Nawa M, Nakahama KI, Ishigami-Yuasa M, Kagechika H, Sugimura H, Iwasa H, Arimoto-Matsuzaki K, Nishina H, Hata Y.

CSE1L promotes nuclear accumulation of transcriptional coactivator TAZ and enhances invasiveness of human cancer cells.
J Biol. Chem. 297, 100803 (2021)
PMID: 34022224

14. Takayama KI, Honma T, Suzuki T, Kondoh Y, Osada H, Suzuki Y, Yoshida M, Inoue S.

Targeting Epigenetic and Posttranscriptional Gene Regulation by PSF Impairs Hormone Therapy-Refractory Cancer Growth.
Cancer Res. 81, 3495-3508 (2021)
PMID: 33975881

15. Yoshida K, Kondoh Y, Nakano T, Bolortuya B, Kawabata S, Iwahashi F, Nagano E, Osada H.

New abscisic acid derivatives revealed adequate regulation of stomatal, transcriptional, and developmental responses to conquer drought.
ACS Chem. Biol. 16, 1566-1575 (2021)
PMID: 34379974

16. Nakatani K, Maehama T, Nishio M, Otani J, Yamaguchi K, Fukumoto M, Hikasa H, Hagiwara S, Nishina H, Mak TW, Honma T, Kondoh Y, Osada H, Yoshida M, Suzuki A.

Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.
Cancer Sci. 112, 4303-4316 (2021)
PMID: 34289205

17. Sakamoto T, Fukui Y, Kondoh Y, Honda K, Shimizu T, Hara T, Hayashi T, Saitoh Y, Murakami Y, Inoue J, Kaneko S, Osada H, Seiki M.
    Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock.
    Commun. Biol. 4, 1165 (2021)
    PMID: 34621018
18. Moon JY, Adams E, Miyazaki T, Kondoh Y, Muroi M, Watanabe N, Osada H, Shin R.
    Cesium tolerance is enhanced by a chemical which binds to BETA- GLUCOSIDASE 23 in Arabidopsis thaliana.
    Sci. Rep. 11, 21109 (2021)
    PMID: 34702872
19. Yoshida J, Ohishi T, Abe H, Ohba S, Inoue H, Usami I, Amemiya M, Oriez R, Sakashita C, Dan S, Sugawara M, Kawaguchi T, Ueno J, Asano Y, Ikeda A, Takamatsu M, Amori G, Kondoh Y, Honda K, Osada H, Noda T, Watanabe T, Shimizu T, Shibasaki M, Kawada M.
    Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.
    iScience 24, 103497 (2021)
    PMID: 34934919
20. Yoshioka H, Kawamura T, Muroi M, Kondoh Y, Honda K, Kawatani M, Aono H, Waldmann H, Watanabe N, Osada H.
    Identification of a small molecule that enhances ferroptosis via inhibition of FSP1.
    ACS Chem. Biol. 17, 483-491 (2022)
    PMID: 35128925
    プレスリリース

代表的な論文

1. Soeda Y, Yoshikawa M, Almeida OF, Sumioka A, Maeda S, Osada H, Kondoh Y, Saito A, Miyasaka T, Kimura T, Suzuki M, Koyama H, Yoshiike Y, Sugimoto H, Ihara Y, *Takashima A.
   Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups.
   Nat. Commun. 6, 10216 (2015)
   PMID: 26671725
2. Kondoh Y, Honda K, *Osada H.
   Construction and application of a photo-cross-linked chemical array.
   Methods Mol. Biol. 1263, 29-41 (2015)
   PMID: 25618334
3. Kondoh Y, Honda K, Hiranuma S, Hayashi T, Shimizu T, Watanabe N, *Osada H.
   Comparative chemical array screening for p38γ/δ MAPK inhibitors using a single gatekeeper residue difference between p38α/β and p38γ/δ.
   Sci. Rep. 6, 29881 (2016)
   PMID: 27431267
4. Maeda K, Nakajima Y, Motoyama T, Kondoh Y, Kawamura T, Kanamaru K, Ohsato S, Nishiuchi T, Yoshida M, Osada H, Kobayashi T, *Kimura M.
   Identification of a trichothecene production inhibitor by chemical array and library screening using trichodiene synthase as a target protein.
   Pestic. Biochem. Physiol. 138, 1-7 (2017)
   PMID: 28456298
5. Kaneko M, Futamura Y, Tsukuda S, Kondoh Y, Sekine T, Hirano H, Fukano K, Ohashi H, Saso W, Morishita R, Matsunaga S, Kawai F, Ryo A, Park SY, Suzuki R, Aizaki H, Ohtani N, Sureau C, Wakita T, Osada H, *Watashi K.
   Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide.
   Sci. Rep. 8, 2769 (2018)
   PMID: 29426822