Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists.
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.
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Jina
J
Kim
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Seo Yeon
SY
Woo
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Chun Young
CY
Im
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital , Daegu 41404, Korea.
Eun Kyung
EK
Yoo
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital , Daegu 41404, Korea.
Seungmi
S
Lee
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Hyo-Ji
HJ
Kim
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Hee-Jong
HJ
Hwang
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Joong-Heui
JH
Cho
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Won Seok
WS
Lee
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Heeseok
H
Yoon
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Shinae
S
Kim
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Oh-Bin
OB
Kwon
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Hayoung
H
Hwang
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Kyung-Hee
KH
Kim
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital , Daegu 41404, Korea.|Department of Internal Medicine, School of Medicine, Kyungpook National University , Daegu 41944, Korea.
Jae-Han
JH
Jeon
Department of Nuclear Medicine, School of Medicine, Kyungpook National University , Daegu 41944, Korea.
Thoudam Debraj
TD
Singh
Korea Bio-Medical Science Institute , Seoul 06106, Republic of Korea.
Sang Wook
SW
Kim
Korea Bio-Medical Science Institute , Seoul 06106, Republic of Korea.
Sung Yeoun
SY
Hwang
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University , Gwangju 61186, Republic of Korea.
Hueng-Sik
HS
Choi
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital , Daegu 41404, Korea.|Department of Internal Medicine, School of Medicine, Kyungpook National University , Daegu 41944, Korea.
In-Kyu
IK
Lee
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Seong Heon
SH
Kim
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital , Daegu 41404, Korea.|Department of Nuclear Medicine, School of Medicine, Kyungpook National University , Daegu 41944, Korea.
Yong Hyun
YH
Jeon
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.
Jungwook
J
Chin
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Korea.|Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital , Daegu 41404, Korea.
Sung Jin
SJ
Cho
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C490917:ESRRG protein, human; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene