title: Anticancer activity of a novel small molecule tubulin inhibitor STK899704.
abstract: We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.|Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
authors.forename: Krisada
authors.initials: K
authors.lastname: Sakchaisri
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Kim
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Nak Kyun
authors.initials: NK
authors.lastname: Soung
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Tae Woong
authors.initials: TW
authors.lastname: Choi
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Chan-Mi
authors.initials: CM
authors.lastname: Park
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Naraganahalli R
authors.initials: NR
authors.lastname: Thimmegowda
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Phil Young
authors.initials: PY
authors.lastname: Lee
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Bettaswamigowda
authors.initials: B
authors.lastname: Shwetha
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Ganipisetti
authors.initials: G
authors.lastname: Srinivasrao
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.|The Key Laboratory of Enzyme & Protein Technology (KLEPT), VNU University of Science, Vietnam National University, Hanoi, Vietnam.
authors.forename: Thi Thu Huong
authors.initials: TT
authors.lastname: Pham
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Jang
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Hye-Won
authors.initials: HW
authors.lastname: Yum
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences and Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D058105:Polymerization / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D014404:Tubulin; D050257:Tubulin Modulators; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C000622362:STK899704; C517009:CDC25C protein, human