Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer

Youngchai Son; Jaeyeal Kim; Yongchan Kim; Sung Gil Chi; Tackhoon Kim; Jinha Yu

doi:10.1016/j.bioorg.2022.106274

Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer

Youngchai Son, Jaeyeal Kim, Yongchan Kim, Sung Gil Chi, Tackhoon Kim, Jinha Yu

Department of Life Sciences

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

3 Citations (Scopus)

Abstract

Disruption of protein–protein interaction between transcriptional enhancer factor (TEA)-domain (TEAD; a transcription factor) and its co-activator Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is a potential therapeutic strategy against various types of solid tumors. Based on hit compound 8 and 9a, hydrazone derivatives with dioxo-benzo[d]isothiazole (9b–n) and oxime ester (10a-s) or amide derivatives (11a-r) with dioxo-benzo[b]thiophene were designed and synthesized as novel TEAD-YAP interaction inhibitors. Amide derivative 11q exhibited a higher potency in inhibiting TEAD-YAP reporter expression activity (IC₅₀ = 12.7 μM), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI₅₀ = 3.2 μM), and anchorage-independent growth in soft agar. Molecular docking analysis suggested that the newly synthesized compounds bound to interface 2 of TEAD had lower docking scores compared to the compounds that bind to interface 3; moreover, they were predicted to overlap with YAP. Therefore, we identified 11q as an attractive therapeutic agent for treating solid tumors overexpressing YAP/TAZ.

Original language	English
Article number	106274
Journal	Bioorganic Chemistry
Volume	131
DOIs	https://doi.org/10.1016/j.bioorg.2022.106274
Publication status	Published - 2023 Feb

Bibliographical note

Funding Information:
We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K.

Funding Information:
We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

Anticancer
Dioxo-benzo[b]thiophene scaffold
Protein-protein interaction inhibitor
YAP/TAZ-TEAD

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

UN SDGs

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

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10.1016/j.bioorg.2022.106274

Cite this

@article{2161829b3e85474eb04d7915a1873219,

title = "Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer",

abstract = "Disruption of protein–protein interaction between transcriptional enhancer factor (TEA)-domain (TEAD; a transcription factor) and its co-activator Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is a potential therapeutic strategy against various types of solid tumors. Based on hit compound 8 and 9a, hydrazone derivatives with dioxo-benzo[d]isothiazole (9b–n) and oxime ester (10a-s) or amide derivatives (11a-r) with dioxo-benzo[b]thiophene were designed and synthesized as novel TEAD-YAP interaction inhibitors. Amide derivative 11q exhibited a higher potency in inhibiting TEAD-YAP reporter expression activity (IC50 = 12.7 μM), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI50 = 3.2 μM), and anchorage-independent growth in soft agar. Molecular docking analysis suggested that the newly synthesized compounds bound to interface 2 of TEAD had lower docking scores compared to the compounds that bind to interface 3; moreover, they were predicted to overlap with YAP. Therefore, we identified 11q as an attractive therapeutic agent for treating solid tumors overexpressing YAP/TAZ.",

keywords = "Anticancer, Dioxo-benzo[b]thiophene scaffold, Protein-protein interaction inhibitor, YAP/TAZ-TEAD",

author = "Youngchai Son and Jaeyeal Kim and Yongchan Kim and Chi, {Sung Gil} and Tackhoon Kim and Jinha Yu",

note = "Funding Information: We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K. Funding Information: We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

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doi = "10.1016/j.bioorg.2022.106274",

language = "English",

volume = "131",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

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AU - Son, Youngchai

AU - Kim, Jaeyeal

AU - Kim, Yongchan

AU - Chi, Sung Gil

AU - Kim, Tackhoon

AU - Yu, Jinha

N1 - Funding Information: We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K. Funding Information: We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2023/2

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N2 - Disruption of protein–protein interaction between transcriptional enhancer factor (TEA)-domain (TEAD; a transcription factor) and its co-activator Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is a potential therapeutic strategy against various types of solid tumors. Based on hit compound 8 and 9a, hydrazone derivatives with dioxo-benzo[d]isothiazole (9b–n) and oxime ester (10a-s) or amide derivatives (11a-r) with dioxo-benzo[b]thiophene were designed and synthesized as novel TEAD-YAP interaction inhibitors. Amide derivative 11q exhibited a higher potency in inhibiting TEAD-YAP reporter expression activity (IC50 = 12.7 μM), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI50 = 3.2 μM), and anchorage-independent growth in soft agar. Molecular docking analysis suggested that the newly synthesized compounds bound to interface 2 of TEAD had lower docking scores compared to the compounds that bind to interface 3; moreover, they were predicted to overlap with YAP. Therefore, we identified 11q as an attractive therapeutic agent for treating solid tumors overexpressing YAP/TAZ.

AB - Disruption of protein–protein interaction between transcriptional enhancer factor (TEA)-domain (TEAD; a transcription factor) and its co-activator Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is a potential therapeutic strategy against various types of solid tumors. Based on hit compound 8 and 9a, hydrazone derivatives with dioxo-benzo[d]isothiazole (9b–n) and oxime ester (10a-s) or amide derivatives (11a-r) with dioxo-benzo[b]thiophene were designed and synthesized as novel TEAD-YAP interaction inhibitors. Amide derivative 11q exhibited a higher potency in inhibiting TEAD-YAP reporter expression activity (IC50 = 12.7 μM), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI50 = 3.2 μM), and anchorage-independent growth in soft agar. Molecular docking analysis suggested that the newly synthesized compounds bound to interface 2 of TEAD had lower docking scores compared to the compounds that bind to interface 3; moreover, they were predicted to overlap with YAP. Therefore, we identified 11q as an attractive therapeutic agent for treating solid tumors overexpressing YAP/TAZ.

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KW - Dioxo-benzo[b]thiophene scaffold

KW - Protein-protein interaction inhibitor

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DO - 10.1016/j.bioorg.2022.106274

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VL - 131

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

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ER -

Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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