Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin
Resource
J. Med. Chem., 59(18), 8521-8534
Journal
Journal of Medicinal Chemistry
Pages
8521-8534
Date Issued
2016
Date
2016
Author(s)
Kuo, Ting-Chun
Li, Ling-Wei
Liu, Jyung-Hurng
Cheng, Ting-Jen
Wang, Chia-Jen
Hung, Pei-Fang
HSUAN-YU CHEN
Hong, Tse-Ming
Hsu, Yuan-Ling
Wong, Chi-Huey
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.
SDGs
Other Subjects
2 (4 butoxyphenyl) 9 (2 methoxyphenyl) 8 oxopurine 6 carboxamide; 2 (4 ethoxyphenyl) 9 (2 methoxyphenyl) 8 oxopurine 6 carboxamide; 2 (4 ethoxyphenyl) 9 (3 carboxy)phenyl 8 oxopurine 6 carboxamide; 2 (4 ethoxyphenyl) 9 (3 methoxycarbonyl)phenyl 8 oxopurine 6 carboxamide; 2 (4 ethoxyphenyl) 9 (4 methoxycarbonyl)phenyl 8 oxopurine 6 carboxamide; 2 (4 ethoxyphenyl) 9 [3 (5 tert butoxycarbonylamino)pentylcarbomoyl]phenyl 8 oxopurine 6 carboxamide; 2 (4 hexoxyphenyl) 9 (2 methoxyphenyl) 8 oxopurine 6 carboxamide; 2 (4 hydroxyphenyl) 9 (2 methoxyphenyl) 8 oxopurine 6 carboxamide; 2 biphenyl 9 (3 methoxycarbonylphenyl) 8 oxopurine 6 carboxamide; antineoplastic agent; caspase 3; katanin protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; nocodazole; paclitaxel; protein; purine derivative; unclassified drug; vincristine; adenosine triphosphatase; antineoplastic agent; katanin; purine derivative; stress activated protein kinase; A549 cell line; animal experiment; animal model; apoptosis; Article; cancer cell; carbon nuclear magnetic resonance; cell cycle M phase; controlled study; drug mechanism; drug protein binding; drug synthesis; G2 phase cell cycle checkpoint; h1975 lung cancer cell line; high throughput screening; human; human cell; in vivo study; lung cancer; microtubule; microtubule assembly; mouse; nonhuman; pharmacophore; protein structure; quantitative structure activity relation; small cell lung cancer; tumor volume; Carcinoma, Non-Small-Cell Lung; cell cycle; cell death; chemistry; drug effects; Lung Neoplasms; metabolism; microtubule; pathology; tumor cell line; Adenosine Triphosphatases; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Death; Cell Line, Tumor; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Microtubules; Purines