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4. Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model

Author

Kaseda, Shota, primary, Sannomiya, Yuya, additional, Horizono, Jun, additional, Kuwazuru, Jun, additional, Suico, Mary Ann, additional, Ogi, Sayaka, additional, Sasaki, Ryoko, additional, Sunamoto, Hidetoshi, additional, Fukiya, Hirohiko, additional, Nishiyama, Hayato, additional, Kamura, Misato, additional, Niinou, Saki, additional, Koyama, Yuimi, additional, Nara, Futoshi, additional, Shuto, Tsuyoshi, additional, Onuma, Kazuhiro, additional, and Kai, Hirofumi, additional

Published
2022
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5. Efficacy of Keap1-Nrf2 protein-protein interaction inhibitor for glomerulosclerosis in mouse model of chronic kidney disease

Author

Kaseda, Shota, primary, Sannomiya, Yuya, additional, Horizono, Jun, additional, Kuwazuru, Jun, additional, Suico, Mary Ann, additional, Ogi, Sayaka, additional, Sasaki, Ryoko, additional, Sunamoto, Hidetoshi, additional, Fukiya, Hirohiko, additional, Nishiyama, Hayato, additional, Kamura, Misato, additional, Nara, Futoshi, additional, Shuto, Tsuyoshi, additional, Onuma, Kazuhiro, additional, and Kai, Hirofumi, additional

Published
2022
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6. Novel Oral Derivative UD-017, a Highly Selective CDK7 Inhibitor, Exhibits Anticancer Activity by Inducing Cell-Cycle Arrest and Apoptosis in Human Colorectal Cancer

Author

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, and Yoneda, Kenji

Subjects
CDK7 inhibitor, HCT-116, UD-017, colorectal cancer
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.

Published
2020

13. Preclinical in vitro and in vivo evaluation of antitumor activity of UD-017, a novel selective and orally available CDK7 inhibitor, in colorectal cancer.

Author

Ogi, Sayaka, primary, Aga, Yasuhiro, additional, Onuma, Kazuhiro, additional, Sunamoto, Hidetoshi, additional, Matsushita, Takashi, additional, Ogawa, Ayumi, additional, Hasegawa, Tohru, additional, Kono, Shigeyuki, additional, Iwase, Noriaki, additional, Tokunaga, Yasunori, additional, and Ushiyama, Shigeru, additional

Published
2017
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15. Novel Oral Derivative UD-017, a Highly Selective CDK7 Inhibitor, Exhibits Anticancer Activity by Inducing Cell-Cycle Arrest and Apoptosis in Human Colorectal Cancer

Author

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, 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, and Yoneda, Kenji

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.

16. Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model.

Author

Kaseda S, Sannomiya Y, Horizono J, Kuwazuru J, Suico MA, Ogi S, Sasaki R, Sunamoto H, Fukiya H, Nishiyama H, Kamura M, Niinou S, Koyama Y, Nara F, Shuto T, Onuma K, and Kai H

Subjects
Animals, Disease Models, Animal, Mice, Oleanolic Acid analogs & derivatives, Oleanolic Acid pharmacology, Phenotype, Kelch-Like ECH-Associated Protein 1 antagonists & inhibitors, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, NF-E2-Related Factor 2 agonists, NF-E2-Related Factor 2 antagonists & inhibitors, NF-E2-Related Factor 2 metabolism, Nephritis, Hereditary drug therapy, Nephritis, Hereditary metabolism, Renal Insufficiency, Chronic
Abstract

Background: Bardoxolone methyl activates nuclear factor erythroid 2-related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored., Methods: We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model ( Col4a5 -G5X)., Results: Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change., Conclusions: UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD., Competing Interests: H. Kai received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. S. Kaseda received research funding from the Japan Society for the Promotion of Science. T. Shuto reports received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Published
2021
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