Novel Oral Derivative UD-017, a Highly Selective CDK7 Inhibitor, Exhibits Anticancer Activity by Inducing Cell-Cycle Arrest and Apoptosis in Human Colorectal Cancer

アクセス数 : 655
ダウンロード数 : 137

今月のアクセス数 : 13
今月のダウンロード数 : 6
File
HiroshimaJMedSci_69_23.pdf 1.06 MB 種類 : fulltext
Title ( eng )
Novel Oral Derivative UD-017, a Highly Selective CDK7 Inhibitor, Exhibits Anticancer Activity by Inducing Cell-Cycle Arrest and Apoptosis in Human Colorectal Cancer
Creator
Aga Yasuhiro
Matsushita Takashi
Ogi Sayaka
Onuma Kazuhiro
Sunamoto Hidetoshi
Ogawa Ayumi
Kono Shigeyuki
Iwase Noriaki
Tokunaga Yasunori
Ushiyama Shigeru
Nara Futoshi
Konno Yasushi
Yoneda Kenji
Source Title
Hiroshima Journal of Medical Sciences
Volume 69
Issue 1
Start Page 23
End Page 31
Journal Identifire
[PISSN] 0018-2052
[EISSN] 2433-7668
[NCID] AA00664312
Abstract
Objective: This study aimed to investigate the anticancer profile of a new cyclin-dependent kinase 7 (CDK7) inhibitor, UD-017, by examining its mechanism of action using HCT-116 colorectal cancer cells.
Methods: The anticancer properties of UD-017 were assessed using several assays, including in vitro kinase, proliferation, and apoptosis assays, western blot analysis, and an in vivo xenograft mouse model.
Results: UD-017 significantly inhibited CDK7 activity (IC50 = 16 nM) with high selectivity in an in vitro kinase assay testing a panel of over 300 proteins and lipid kinases. UD-017 also inhibited the growth of HCT-116 cells (GI50 = 19 nM) and inhibited the phosphorylation of various downstream mediators of CDK7 signaling. In cell cycle and apoptosis assays using HCT-116 cells, UD-017 increased the number of cells in both G1 and G2/M phases and induced apoptosis. In vivo, UD-017 inhibited tumor growth in an HCT-116 xenograft mouse model by 33%, 64%, and 88% at doses of 25, 50, and 100 mg/kg, respectively, with clear dose-dependency. Co-administration of 5-FU and 50 mg/kg UD-017 had a strong synergistic effect, as reflected in the complete inhibition of tumor growth.
Conclusion: CDK7 may play a major role in colorectal cancer growth by regulating the cell cycle and apoptosis. UD-017 is a promising candidate therapeutic agent for the treatment of cancer involving CDK7 signaling.
Keywords
UD-017
CDK7 inhibitor
colorectal cancer
HCT-116
Language
eng
Resource Type departmental bulletin paper
Publisher
Hiroshima University Medical Press
Date of Issued 2020-03
Rights
Copyright (c) 2020 Hiroshima University Medical Press
Publish Type Version of Record
Access Rights open access
Source Identifier
[ISSN] 0018-2052
[ISSN] 2433-7668
[NCID] AA00664312
[DOI] 10.24811/hjms.69.1_23
[DOI] https://doi.org/10.24811/hjms.69.1_23