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.

Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

“…Recombinant human IL-6 is obtained from Prospec Protein Specialists (East Brunswick, NJ, USA, Cat#cyt-213), and GSK5182 was synthesized as previously described [ 28 , 34 , 35 , 45 ]. For immunohistochemical staining of endogenous ERRγ, rabbit anti-ERRγ serum was generated using a peptide (404-AGQHMEDPRRAGKMLM-419) from mouse ERRγ helix 9 [ 46 ] (AbFrontier/Young in Frontier, Seoul, Korea).…”

“…It also involved in iron homeostasis through regulating the expression of hepatic iron regulating hormone, hepcidin [ 32 ]. Although ERRγ is constitutively active, it exhibits limited affinity toward many synthetic ligands, including 4-hydroxytamoxifen (4-OHT), which act as an inverse agonist by blocking the binding of ERRγ to response elements on the regulatory regions of target genes [ 33 , 34 , 35 ].…”

A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer

“…We recently reported that the selective ERRg inverse agonist GSK5182 enhances NIS-mediated radioiodine uptake in ATC cells with either KRAS or BRAF mutations, promoting enhanced radioiodine therapy responsiveness in vitro (9). Toward discovering novel ERRg inverse agonists, we also reported several lead optimization studies including 4-hydroxytamoxifen analogue synthesis and biological evaluation (10,11). This finding provided a rationale for exploring new ERRg inverse agonists that effectively enhance NIS function in vivo and show potential for clinical translation to patients with ATC.…”

Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

“…Kim et al reported the short and efficient synthesis of alcohol analogues of tamoxifen via Mitsunobu reaction and biological evaluation towards estrogen-related receptor γ (ERRγ) inverse agonist (Scheme 94). [98] The synthesis involved the Mitsunobu reaction of 482 with corresponding alcohols to afford 483 in 15-99% yields followed by reduction of methyl ester group and deprotection of pivaloyl group (piv) by LiAlH 4 gave 484 in 3-99% yield as Z-isomer. Corresponding Z-485 was synthesized in 17% yield as HCl salt in the presence of 1 M aqueous HCl mixed with CH 2 Cl 2 /CH 3 OH solution.…”