Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity

Takuya Okada; Kaho Yamabe; Michiko Jo; Yuko Sakajiri; Tomokazu Shibata; Ryusuke Sawada; Yoshihiro Yamanishi; Daisuke Kanayama; Hisashi Mori; Mineyuki Mizuguchi; Takayuki Obita; Yuko Nabeshima; Keiichi Koizumi; Naoki Toyooka

doi:10.1016/j.bmcl.2023.129438

Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity

Takuya Okada^*, Kaho Yamabe, Michiko Jo, Yuko Sakajiri, Tomokazu Shibata, Ryusuke Sawada, Yoshihiro Yamanishi, Daisuke Kanayama, Hisashi Mori, Mineyuki Mizuguchi, Takayuki Obita, Yuko Nabeshima, Keiichi Koizumi, Naoki Toyooka

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC₅₀ of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.

Original language	English
Article number	129438
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	93
DOIs	https://doi.org/10.1016/j.bmcl.2023.129438
State	Published - 2023/09/01

Keywords

Docking-simulation
GLS1 inhibitor
Glutaminase
Structure–activity relationship
Thiaziazole

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2023.129438

Cite this

Okada, T., Yamabe, K., Jo, M., Sakajiri, Y., Shibata, T., Sawada, R., Yamanishi, Y., Kanayama, D., Mori, H., Mizuguchi, M., Obita, T., Nabeshima, Y., Koizumi, K., & Toyooka, N. (2023). Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity. Bioorganic and Medicinal Chemistry Letters, 93, Article 129438. https://doi.org/10.1016/j.bmcl.2023.129438

@article{20dc946c77734e7fa9efebd4bcaf0fda,

title = "Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity",

abstract = "GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.",

keywords = "Docking-simulation, GLS1 inhibitor, Glutaminase, Structure–activity relationship, Thiaziazole",

author = "Takuya Okada and Kaho Yamabe and Michiko Jo and Yuko Sakajiri and Tomokazu Shibata and Ryusuke Sawada and Yoshihiro Yamanishi and Daisuke Kanayama and Hisashi Mori and Mineyuki Mizuguchi and Takayuki Obita and Yuko Nabeshima and Keiichi Koizumi and Naoki Toyooka",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd",

year = "2023",

month = sep,

day = "1",

doi = "10.1016/j.bmcl.2023.129438",

language = "英語",

volume = "93",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

}

Okada, T, Yamabe, K, Jo, M, Sakajiri, Y, Shibata, T, Sawada, R, Yamanishi, Y, Kanayama, D, Mori, H , Mizuguchi, M , Obita, T, Nabeshima, Y, Koizumi, K & Toyooka, N 2023, 'Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity', Bioorganic and Medicinal Chemistry Letters, vol. 93, 129438. https://doi.org/10.1016/j.bmcl.2023.129438

TY - JOUR

T1 - Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity

AU - Okada, Takuya

AU - Yamabe, Kaho

AU - Jo, Michiko

AU - Sakajiri, Yuko

AU - Shibata, Tomokazu

AU - Sawada, Ryusuke

AU - Yamanishi, Yoshihiro

AU - Kanayama, Daisuke

AU - Mori, Hisashi

AU - Mizuguchi, Mineyuki

AU - Obita, Takayuki

AU - Nabeshima, Yuko

AU - Koizumi, Keiichi

AU - Toyooka, Naoki

PY - 2023/9/1

Y1 - 2023/9/1

N2 - GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.

AB - GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.

KW - Docking-simulation

KW - GLS1 inhibitor

KW - Glutaminase

KW - Structure–activity relationship

KW - Thiaziazole

UR - http://www.scopus.com/inward/record.url?scp=85167412512&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2023.129438

DO - 10.1016/j.bmcl.2023.129438

M3 - 学術論文

C2 - 37549852

AN - SCOPUS:85167412512

SN - 0960-894X

VL - 93

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 129438

ER -

Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this