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

Aga Yasuhiro

Matsushita Takashi

Ogi Sayaka

Onuma Kazuhiro

Sunamoto Hidetoshi

Ogawa Ayumi

Kono Shigeyuki

Iwase Noriaki

Tokunaga Yasunori

Ushiyama Shigeru

Nara Futoshi

Konno Yasushi

Yoshizumi Masao

Kokubo Hiroki

Yoneda Kenji

Hiroshima Journal of Medical Sciences

[PISSN] 0018-2052

[EISSN] 2433-7668

[NCID] AA00664312

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.

UD-017

CDK7 inhibitor

colorectal cancer

HCT-116

英語

Hiroshima University Medical Press

Copyright (c) 2020 Hiroshima University Medical Press

[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