Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin

Ting Chun Kuo; Ling Wei Li; Szu Hua Pan; Jim Min Fang; Jyung Hurng Liu; Ting Jen Cheng; Chia Jen Wang; Pei Fang Hung; Hsuan Yu Chen; Tse Ming Hong; Yuan Ling Hsu; Chi Huey Wong; Pan Chyr Yang

doi:10.1021/acs.jmedchem.6b00797

Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin

Ting Chun Kuo, Ling Wei Li, Szu Hua Pan, Jim Min Fang, Jyung Hurng Liu, Ting Jen Cheng, Chia Jen Wang, Pei Fang Hung, Hsuan Yu Chen, Tse Ming Hong, Yuan Ling Hsu, Chi Huey Wong, Pan Chyr Yang

Institute of Clinical Medicine

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

Abstract

Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.

Original language	English
Pages (from-to)	8521-8534
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00797
Publication status	Published - 2016 Sept 22

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Kuo, T. C., Li, L. W., Pan, S. H., Fang, J. M., Liu, J. H., Cheng, T. J., Wang, C. J., Hung, P. F., Chen, H. Y., Hong, T. M., Hsu, Y. L., Wong, C. H., & Yang, P. C. (2016). Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin. Journal of Medicinal Chemistry, 59(18), 8521-8534. https://doi.org/10.1021/acs.jmedchem.6b00797

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abstract = "Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.",

author = "Kuo, {Ting Chun} and Li, {Ling Wei} and Pan, {Szu Hua} and Fang, {Jim Min} and Liu, {Jyung Hurng} and Cheng, {Ting Jen} and Wang, {Chia Jen} and Hung, {Pei Fang} and Chen, {Hsuan Yu} and Hong, {Tse Ming} and Hsu, {Yuan Ling} and Wong, {Chi Huey} and Yang, {Pan Chyr}",

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AU - Liu, Jyung Hurng

AU - Cheng, Ting Jen

AU - Wang, Chia Jen

AU - Hung, Pei Fang

AU - Chen, Hsuan Yu

AU - Hong, Tse Ming

AU - Hsu, Yuan Ling

AU - Wong, Chi Huey

AU - Yang, Pan Chyr

PY - 2016/9/22

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N2 - Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.

AB - Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.

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Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin

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