Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

Jina Kim; Seo Yeon Woo; Chun Young Im; Eun Kyung Yoo; Seungmi Lee; Hyo Ji Kim; Hee Jong Hwang; Joong Heui Cho; Won Seok Lee; Heeseok Yoon; Shinae Kim; Oh Bin Kwon; Hayoung Hwang; Kyung Hee Kim; Jae Han Jeon; Thoudam Debraj Singh; Sang Wook Kim; Sung Yeoun Hwang; Hueng Sik Choi; In Kyu Lee; Seong Heon Kim; Yong Hyun Jeon; Jungwook Chin; Sung Jin Cho

doi:10.1021/acs.jmedchem.6b01204

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

Jina Kim
, Seo Yeon Woo
, Chun Young Im
, Eun Kyung Yoo
, Seungmi Lee
, Hyo Ji Kim
, Hee Jong Hwang
, Joong Heui Cho
, Won Seok Lee
, Heeseok Yoon
, Shinae Kim
, Oh Bin Kwon
, Hayoung Hwang
, Kyung Hee Kim
, Jae Han Jeon
, Thoudam Debraj Singh
, Sang Wook Kim
, Sung Yeoun Hwang
, Hueng Sik Choi
, In Kyu Lee

Seong Heon Kim, Yong Hyun Jeon, Jungwook Chin, Sung Jin Cho

Department of Medicine

Daegu-Gyeongbuk Medical Innovation Foundation
Kyungpook National University
Korea Bio-Medical Science Institute
Chonnam National University

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

23 Scopus citations

Abstract

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

Original language	English
Pages (from-to)	10209-10227
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	22
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01204
State	Published - 23 Nov 2016

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10.1021/acs.jmedchem.6b01204

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Kim, J., Woo, S. Y., Im, C. Y., Yoo, E. K., Lee, S., Kim, H. J., Hwang, H. J., Cho, J. H., Lee, W. S., Yoon, H., Kim, S., Kwon, O. B., Hwang, H., Kim, K. H., Jeon, J. H., Singh, T. D., Kim, S. W., Hwang, S. Y., Choi, H. S., ... Cho, S. J. (2016). Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists. Journal of Medicinal Chemistry, 59(22), 10209-10227. https://doi.org/10.1021/acs.jmedchem.6b01204

@article{4ba5900aec0541f5b4fd1bc6fe6d6b10,

title = "Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists",

abstract = "We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.",

author = "Jina Kim and Woo, \{Seo Yeon\} and Im, \{Chun Young\} and Yoo, \{Eun Kyung\} and Seungmi Lee and Kim, \{Hyo Ji\} and Hwang, \{Hee Jong\} and Cho, \{Joong Heui\} and Lee, \{Won Seok\} and Heeseok Yoon and Shinae Kim and Kwon, \{Oh Bin\} and Hayoung Hwang and Kim, \{Kyung Hee\} and Jeon, \{Jae Han\} and Singh, \{Thoudam Debraj\} and Kim, \{Sang Wook\} and Hwang, \{Sung Yeoun\} and Choi, \{Hueng Sik\} and Lee, \{In Kyu\} and Kim, \{Seong Heon\} and Jeon, \{Yong Hyun\} and Jungwook Chin and Cho, \{Sung Jin\}",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = nov,

day = "23",

doi = "10.1021/acs.jmedchem.6b01204",

language = "English",

volume = "59",

pages = "10209--10227",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Kim, J, Woo, SY, Im, CY, Yoo, EK, Lee, S, Kim, HJ, Hwang, HJ, Cho, JH, Lee, WS, Yoon, H, Kim, S, Kwon, OB, Hwang, H, Kim, KH, Jeon, JH, Singh, TD, Kim, SW, Hwang, SY, Choi, HS, Lee, IK, Kim, SH, Jeon, YH, Chin, J & Cho, SJ 2016, 'Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists', Journal of Medicinal Chemistry, vol. 59, no. 22, pp. 10209-10227. https://doi.org/10.1021/acs.jmedchem.6b01204

TY - JOUR

T1 - Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

AU - Kim, Jina

AU - Woo, Seo Yeon

AU - Im, Chun Young

AU - Yoo, Eun Kyung

AU - Lee, Seungmi

AU - Kim, Hyo Ji

AU - Hwang, Hee Jong

AU - Cho, Joong Heui

AU - Lee, Won Seok

AU - Yoon, Heeseok

AU - Kim, Shinae

AU - Kwon, Oh Bin

AU - Hwang, Hayoung

AU - Kim, Kyung Hee

AU - Jeon, Jae Han

AU - Singh, Thoudam Debraj

AU - Kim, Sang Wook

AU - Hwang, Sung Yeoun

AU - Choi, Hueng Sik

AU - Lee, In Kyu

AU - Kim, Seong Heon

AU - Jeon, Yong Hyun

AU - Chin, Jungwook

AU - Cho, Sung Jin

PY - 2016/11/23

Y1 - 2016/11/23

N2 - We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

AB - We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

UR - https://www.scopus.com/pages/publications/84999791357

U2 - 10.1021/acs.jmedchem.6b01204

DO - 10.1021/acs.jmedchem.6b01204

M3 - Article

C2 - 27805390

AN - SCOPUS:84999791357

SN - 0022-2623

VL - 59

SP - 10209

EP - 10227

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

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