化合物ライブラリーの配付
Distribution of compound libraries

（担当：川田 学）
(Member in charge: Manabu Kawada)

• 標準阻害剤キット (SCADS inhibitor kits)
• 寄託化合物ライブラリー (Deposited compound libraries)

標準阻害剤キット
SCADS inhibitor kits

ライフサイエンスの研究を行う上で、ある特定の機能を持った低分子化合物をツールとして利用するケミカルバイオロジーは強力な武器となる。例えば、ある生命現象に数ある阻害剤の中でAという酵素の低分子阻害剤のみが効果を発揮したとすると、その生命現象には酵素Aが関与する事が推測される。このように阻害剤を用いる事で、これまで謎であった生命現象のメカニズムが明らかになったり、さらにはその生命現象が関与する疾患の分子標的薬の開発に繋がるケースもある。どのような阻害剤が自分の研究に利用可能か簡単に知る事ができれば、研究をスピードアップできるだけでなく、それを用いて新しい発見に至る可能性もある。しかしながら、現在市販されている阻害剤は沢山あり、どれを選択すべきかも含めて、個々の研究室でそれらをライブラリーとして整備するにはあまりにも大変な労力と費用が必要となってしまう。このような状況を打破し、多くの研究者がケミカルバイオロジー研究を容易に行える様に、各種阻害剤を体系的に収集し、これらを標準阻害剤キットとしてまとめ、希望する研究者に提供することによって係る研究を支援する。研究者は、本キットを、注目する標的と既知分子標的との比較、細胞内情報伝達の研究、化合物探索系の評価などに利用できる。

Chemical biology using small compounds with specific functions can have a great power for the research of life science. When a small compound inhibiting an enzyme “A” can only affect a specific phenotype in a experiment, the enzyme “A” is suggested to be involved in the phenotype. Thus, using such small compound inhibitors will unveil underlying mechanisms in unknown phenotypes and also lead to the development of new molecular target drugs for diseases related to the phenotypes. If you easily choose appropriate small compound inhibitors for your research, you can accelerate your research and possibly reach to novel findings. However, there are so many compounds even if commercially available that you should waste power and money to prepare them by yourself. To improve this situation and support chemical biology for many researchers, we systematically collect many small compound inhibitors and distribute them as SCADS inhibitor kits for every researcher who needs them. You can use SCADS inhibitors kits for the evaluation of compound screening systems, the analysis of intracellular signals, the comparison of target molecules in your interest with known target molecules, and so on.

「ご利用研究者の評価結果」
Reported results from users

• 標準阻害剤キットのユーザーレポートその2【Word形式】
  User reports of SCADS inhibitor kits, part 2 (Word file)
• 標準阻害剤キットのユーザーレポート【Word形式】
  User reports of SCADS inhibitor kits (Word file)
• Kit references.doc【Word形式】
  Kit references.doc (Word file)
• アッセイ系一覧
  List of experiments using SCADS inhibitor kits
• 化合物から検索
  Search of data base by compound names

「標準阻害剤キットの内容」
Contents of SCADS inhibitor kits

基本的に標的分子がはっきりとしていて、現在のサイエンスで阻害剤として定着し、バイオプローブとして有用な低分子化合物と既存の制がん剤で構成する。キットは、96wellV底プレートの各wellに阻害剤を濃度2mM* (in DMSO)で5μl (10nmol)分注し作製した。*一部例外あり、化合物リストを参照のこと。

SCADS inhibitor kits consist of small compounds with specific functions that have been used for many published studies and known anti-cancer drugs. Each compound is dissolved in DMSO at 2mM* and dispensed at 5μl (10nmol) in a 96 well v-shape plate. *Some compounds are exceptional, see the following lists.

阻害剤キットの使用方法の例
阻害剤キットのプレート各wellに50% MeOHを95μl加え、阻害剤100μMのストックsolutionを作製する。これをトータル100μlの細胞培養や酵素アッセイ系に10μl添加すると最終濃度10μMとなり、約10回利用可能。

Tip for use of SCADS inhibitor kits
You can prepare stock solution as 100 μM to add 95 μl of 50% MeOH into each well of the kits. If you add 10 μl of the stock solution into total 100 μl assay medium, it becomes as final 10 μM and you can use it for about 10 wells.

【標準阻害剤キットを使用した論文発表」
Publication using SCADS inhibitor kit

• Tokunaga M, Miyamoto Y, Suzuki T, Otani M, Inuki S, Esaki T, Nagao C, Mizuguchi K, Ohno H, Yoneda Y, Okamoto T, Oka M, Matsuura Y (2019). Novel anti-flavivirus drugs targeting the nucleolar distribution of core protein. Virology, 541, 41-51. https://doi.org/10.1016/j.virol.2019.11.015
• Eto S, Saeki K, Yoshitake R, Yoshimoto S, Shinada M, Ikeda N, Kamoto S, Tanaka Y, Kato D, Maeda S, Tsuboi M, Chambers J, Uchida K, Nishimura R, Nakagawa T (2019). Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells, PLoS ONE, 14:6, e0218382. https://doi.org/10.1371/journal.pone.0218382
• Kamata H, Sadahiro S, Yamori T (2019). Discovery of Inhibitors of Membrane Traffic from a Panel of Clinically Effective Anticancer Drugs, Biol Pharm Bull, 42, 814-818. https://doi.org/10.1248/bpb.b18-01026
• Nehwa FJ, Matsui TS, Honghan L, Matsunaga D, Sakaguchi Y, Deguchi S (2019). Multi-well plate cell contraction assay detects negatively correlated cellular responses to pharmacological inhibitors in contractility and migration, Biochemical and Biophysical Research Communications. https://doi.org/10.1016/j.bbrc.2019.10.160
• Fukamachi H, Kim SK, Koh J, Lee HS, Sasaki Y, Yamashita K, Nishikawaji T, Shimada S, Akiyama Y, Byeon SJ, Bae DH, Okuno K, Nakagawa M, Tanioka T, Inokuchi M, Kawachi H, Tsuchiya K, Kojima K, Tokino T, Eishi Y, Kim YS, Kim WH, Yuasa Y, Tanaka S (2019). A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors, J Exp Clin Cancer Res, 38, 127. https://doi.org/10.1186/s13046-019-1121-3
• Qiao Z, Kondo T (2019). Screening of a growth inhibitor library of sarcoma cell lines to identify potent anti-cancer drugs, Journal of Electrophoresis, 63, 1-7. https://doi.org/10.2198/jelectroph.63.1
• Igase M, Shibutani S, Kurogouchi Y, Fujiki N. Hwang CC, Coffey M, Noguchi S, Nemoto Y, Mizuno T (2019). Combination Therapy with Reovirus and ATM Inhibitor Enhances Cell Death and Virus Replication in Canine Melanoma, Molecular Therapy Oncolytics, 15, 49-59. https://doi.org/10.1016/j.omto.2019.08.003
• Yoshitake R, Saeki K, Eto S, Shinada M, Nakano R, Sugiya H, Endo Y, Fujita N, Nishimura R, Nakagawa T (2019). Aberrant expression of the COX2/PGE2 axis is induced by activation of the RAF/MEK/ERK pathway in BRAFV595E canine urothelial carcinoma, bioRxiv. https://doi.org/10.1101/786095
• Fujino S, Ito A. Ohue M, Yasui M, Mizushima T, Doki Y, Mori M, Miyoshi N (2019). Phenotypic heterogeneity of 2D organoid reflects clinical tumor characteristics, Biochemical and Biophysical Research Communications, 513, 332-339. https://doi.org/10.1016/j.bbrc.2019.03.173
• Ishii S, Matsuura A, Itakura E (2019). Identification of a factor controlling lysosomal homeostasis using a novel lysosomal trafficking probe, Sci Rep, 9, 11635. https://doi.org/10.1038/s41598-019-48131-2
• Kurisawa N, Yukawa M, Koshino H, Onodera T, Toda T, Kimura KI (2019). Kolavenic acid analog restores growth in HSET-overproducing fission yeast cells and multipolar mitosis in MDA-MB-231 human cells, Bioorganic and Medical Chemistry. https://doi.org/10.1016/j.bmc.2019.115154
• Okada K, Araki M, Sakashita T, Ma B, Kanada R, Yanagitani N, Horiike A, Koike S, Oh-hara T, Watanabe K, Tamai K, Maemondo M, Nishio M, Ishikawa T, Okuno Y, Fujita N, Katayama R (2019). Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance, EBioMedicine, 41, 105-119. https://doi.org/10.1016/j.ebiom.2019.01.019
• Seno A, Mizutani A, Aizawa K, Onoue R, Masuda J, Ochi N, Taniguchi S, Sota T, Hiramoto Y, Michiue T, Nair N, Seno M (2019). Daunorubicin can eliminate iPS-derived cancer stem cells via ICAD/CAD-independent DNA fragmentation, Cancer Drug Resist, 2, 335-350. http://dx.doi.org/10.20517/cdr.2019.01
• Sato K, Masuda T, Hu Q, Tobo T, Gillaspie S, Niida A, Thornton M, Kuroda Y, Eguchi H, Nakagawa T, Asano K, Mimori K (2019). Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer, EBioMedicine, 44, 387-402. https://doi.org/10.1016/j.ebiom.2019.05.058
• Vu HT, Kobayashi M, Hegazy AM, Tadokoro Y, Ueno M, Kasahara A, Takase Y, Nomura N, Peng H, Ito C, Ino Y, Todo T, Nakada M, Hirao A (2019). Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas Cancer, Sci, 109, 2497-2508. https://doi.org/10.1111/cas.13695
• Oku Y, Nishiya N, Tazawa T, Kobayashi T, Umezawa N, Sugawara Y, Uehara Y (2018). Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP?E2F1?DNA damage response pathway axis, FEBS Open Bio, 8, 1001-1012. https://doi.org/10.1002/2211-5463.12440
• Takahashi A, Seike M, Chiba M, Takahashi S, Nakamichi S, Matsumoto M, Takeuchi S, Minegishi Y, Noro R, Kunugi S, Kubota K, Gemma A (2018). Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer, Sci Rep, 8, 14896. https://doi.org/10.1038/s41598-018-33190-8
• Nakamichi S, Seike M, Miyanaga A, Chiba M, Zou F, Takahashi A, Ishikawa A, Kunugi S, Noro R, Kubota K, Gemma A (2018). Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial?mesenchymal transition is critical in conquering ALK-positive lung cancer Oncotarget 9 (43) 27242-27255 2018 10. 18632/oncotarget.25531
• Fujikake K, Sawada M, Hikita T, Seto Y, Kaneko N, Perez VH, Dohi N, Homma N, Osaga S, Yanagawa Y, Akaike T, Garcia-Verdugo JM, Hattori M, Sobue K, Sawamoto K (2018). Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell? cell Adhesion in the Postnatal Brain, J Neuroscience, 38:19, 4598-4609. https://doi.org/10.1523/JNEUROSCI.1960-17.2018
• Yamaguchi K, Zhu C, Ohsugi T, Yamaguchi Y, Ikenoue T, Furukawa Y (2017). Bidirectional reporter assay using?HAL?promoter and TOPFLASH improves specificity in high?]throughput screening of Wnt inhibitors, Biotechnology Bioengineering, 114, 2868-2882. https://doi.org/10.1002/bit.26394
• Kuroki S, Kobayashi M, Tani H, Miyamoto R, Kurita S, Tamura K, Ono K, Washizu T, Bonkobara M (2017). Selective growth inhibition by suppression of F1Fo ATPase in canine?malignant melanoma cell lines, J Veterinary Pharmacology and Therapeutics, 40, 101-104, https://doi.org/10.1111/jvp.12336
• Tsurumaki H, Katano H, Sato K, Imai R, Niino S, Hirabayashi Y, Ichikawa S (2017). WP1066, a small molecule inhibitor of the JAK/STAT3 pathway, inhibits ceramide glucosyltransferase activity, Biochemical and Biophysical Research Communications, 491, 265-270, https://doi.org/10.1016/j.bbrc.2017.07.115
• Fukushima S, Endo M, Matsumoto Y, Fukushi J, Matsunobu T, Kawaguchi K, Setsu N, IIda K, Yokoyama N, Nakagawa M, Yahiro K, Oda Y, Iwamoto Y, Nakashima Y (2017). Hypoxia-inducible factor 1 alpha is a poor prognostic factor and potential therapeutic target in malignant peripheral nerve sheath tumor, PLoS ONE, 13, e0194508. https://doi.org/10.1371/journal.pone.0178064
• Morimoto‐Kamata R, Yui S (2017). Insulin‐like growth factor‐1 signaling is responsible for cathepsin G‐induced aggregation of breast cancer MCF‐7 cells, Cancer Sci, 108, 1574-1583. https://doi.org/10.1111/cas.13286
• Iwamoto Y, Ishii K, Kanda H, Kato M, Miki M, Kajiwara S, Arima K, Shiraishi T, Sugimura Y (2017). Combination treatment with naftopidil increases the efficacy of radiotherapy in PC-3 human prostate cancer cells, J Cancer Research and Clinical Oncology, 143, 933-939. https://doi.org/10.1007/s00432-017-2367-9
• Honda S, Sadatomi D, Yamamura Y, Nakashioya K, Tanimura S, Takeda K (2017). WP1066 suppresses macrophage cell death induced by inflammasome agonists independently of its inhibitory effect on STAT3, Cancer Sci, 108, 520-527. https://doi.org/10.1111/cas.13154
• Tashiro T, Okuyama H, Endo H, Kawada K, Ashida Y, Ohue M, Sakai Y, Inoue M (2017). In vivo?and?ex vivo?cetuximab sensitivity assay using three-dimensional primary culture system to stratify?KRAS?mutant colorectal cancer, PLoS ONE, 12, e0174151. https://doi.org/10.1371/journal.pone.0174151
• Matsuda Y, Ishiwata T, Yoshimura H, Yamahatsu K, Minamoto T, Arai T (2017). Nestin phosphorylation at threonines 315 and 1299 correlates with proliferation and metastasis of human pancreatic cancer, Cancer Sci, 108, 354-361. https://doi.org/10.1111/cas.13139
• Oku Y, Nishiya N, Tsuda K, Shibazaki M, Maesawa C, Uehara Y (2017). Dynamic Phenotypic Transition of Breast Cancer Cells?In Vitro?Revealed by Self-floating Cell Culture, Anticancer Research, 37, 1793-1797.
• Ogura H, Nagatake-Kobayashi Y, Adachi J, Tomonaga T, Fujita N, Katayama R (2016). TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity, Sci Rep, 7, 5519. https://doi.org/10.1038/s41598-017-05736-9
• Oi T, Asanum K, Matsumine A, Matsubara T, Nakamura T, Iino T, Asanuma Y, Goto M, Okuno K, Kakimoto T, Yada Y, Sudo A (2016). STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma, Int J Oncology, 49, 2275-2284. https://doi.org/10.3892/ijo.2016.3757
• Tsuji-Tamura K, Ogawa M (2016). Inhibition of the PI3K-Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells, J Cell Science, 129, 1165-1178. doi:10.1242/jcs.178434
• Tashiro E, Henmi S, Odake H, Ino S, Imoto M (2016). Involvement of the MEK/ERK pathway in EGF-induced E-cadherin down-regulation, Biochemical and Biophysical Research Communications, 477, 801-806. https://doi.org/10.1016/j.bbrc.2016.06.138
• Matsumoto H, Saitoh H (2016). Puromycin induces SUMO and ubiquitin redistribution upon proteasome inhibition, Biochemical and Biophysical Research Communications, 476, 153-158. https://doi.org/10.1016/j.bbrc.2016.05.025
• Lou C, Yokoyama S, Abdelhamed S, Saiki I, Hayakawa Y (2016). Targeting the ataxia telangiectasia mutated pathway for effective therapy against hirsutine-resistant breast cancer cells, Oncology Letters, 12, 295-300. https://doi.org/10.3892/ol.2016.4554
• Kume K, Ikeda M, Miura S, Ito K, Sato KA, Ohmori Y, Endo F, Katagiri H, Ishida K, Ito C, Iwaya T, Nishizuka SS (2016). α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via?TAF15, Sci Rep, 6, 25895. https://doi.org/10.1038/srep25895
• Inagaki Y, Matsumoto Y, Tang W, Sekimizu K (2016). Dividing phase-dependent cytotoxicity profiling of human embryonic lung fibroblast identifies candidate anticancer reagents, Drugs Discoveries & Therapeutics, 10, 195-200. https://doi.org/10.5582/ddt.2016.01049

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「標準阻害剤キット配付の条件及び注意事項」
Requirements and cautions for distribution of SCADS inhibitor kits

標準阻害剤キット（以下キット）の分与は、キットの分与希望者が下記条件を遵守することを前提と致します。

Researcher who wants to use SCADS inhibitor kits must comply with the following rules.

寄託化合物ライブラリー
Deposited compound libraries

化学療法基盤支援活動班では、寄託化合物ライブラリーに収録される化合物を全国の研究者から募集します。 寄託化合物ライブラリーを拡充することにより、化合物が有する未知の生理活性を知りたい研究者と、ある特定の生理活性を有する化合物を探索したい研究者の双方への支援が実現します。 寄託化合物ライブラリーに収録された化合物は、当班が現在用意する評価系以外の評価系（注：当班が新たに用意した評価系、寄託化合物ライブラリーの提供を受けた研究者が用意した評価系を含む。）にかけられ、その結果は逐次、化合物を寄託した研究者に報告されます。 また、本ライブラリーを、さまざまな分子標的スクリーニングを行っている研究者に提供することにより、研究者がリード化合物を取得するための探索研究を支援します。当班は、本ライブラリーの提供を希望する研究者を審査し、一定の基準を満たした研究者に配付します。寄託化合物ライブラリーの提供を受けた研究者は、評価結果をすみやかに当班に報告し、当班はその評価結果を化合物を寄託した研究者に通知します。寄託化合物ライブラリーの提供を希望する研究者は、原則、科学研究費補助金を受給している日本国内の研究者（研究代表者または研究分担者）に限らせて頂きます。

We call for various compounds that can be deposited to this library from all throughout Japan. Expanding the deposited compound libraries, we can greatly support every researcher who wants to know novel functions of a compound or who wants to find a compound with specific functions. Compounds deposited to this library can be evaluated on various experiments prepared by us and researchers who request to use them, and the results must be reported to a researcher who deposited his/her compounds. Through distributing deposited compounds libraries, we can support researchers who search for a lead compound to a designated molecular target. We decide whether the researcher requesting the library is appropriate for the distribution, when we get a request from the researcher. Once the researcher is allowed to use the library, he/she must promptly assess experiments and feedback the results to us. We then report the results to each depositor of compounds. The researcher who wants to use the deposited compound libraries must get grants in aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan (KAKENHI).

「寄託化合物ライブラリー使用の条件及び注意事項 」
Requirements and cautions for distribution of deposited compound libraries

ライブラリーへの化合物寄託者（以下「寄託者」）および寄託化合物ライブラリーの利用者（以下「利用者」）の権利を守るために、当班が定めた下記条件を利用者が遵守することを前提とする。

Researcher who wants to deposit compounds (depositor) and who wants to use deposited compounds libraries (user) must comply with the following rules to protect their rights.

本ライブラリーを用いた成果発表・特許出願については、当班の仲介のもと利用者と寄託者で協議する。当班は得られた成果等について知的財産権を主張しないが、使用結果の公表の際には、当班に謝意を表するものとする。また、公表した旨を当班に報告する。

For publication and patent application using the deposited compound libraries, both depositor and user must negotiate about it after we mediate the occasion. We cannot claim any rights for the results obtained by depositor and user, but they must express the acknowledgements to us and report the publication and patent application.

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