Abstract
(E/Z)-3-(4-((E)-1-(4-Hydroxyphenyl)-2-phenylbut-1-enyl)phenyl)acrylic acid (GW7604) as a derivative of (Z)-4-hydroxytamoxifen (4-OHT) was linked by diaminoalkane spacers to molecules that are known binders to the coactivator binding site (benzimidazole or thioxo-quinazolinone scaffolds). With this modification, an optimization of the pharmacological profile was achieved. The most active thioxo-quinazolinone derivative 16 showed extraordinarily high affinity to the estrogen receptor (ER) β (RBA = 110%), inhibited effectively the coactivator recruitment (IC50 = 20.88 nM (ERα) and 28.34 nM (ERβ)), acted as a pure estradiol (E2) antagonist in a transactivation assay (IC50 = 18.5 nM (ERα) and 7.5 nM (ERβ)), and downregulated the ERα content in MCF-7 cells with an efficacy of 60% at 1 μM. The cytotoxicity was restricted to hormone-dependent MCF-7 (IC50 = 4.2 nM) and tamoxifen-resistant MCF-7TamR cells (IC50 = 476.6 nM). The compounds bearing a thioxo-quinazolinone moiety can therefore be assigned as pure E2-antagonistic selective ER degraders/downregulators. By contrast, the benzimidazole derivatives acted solely as pure antagonists without degradation of the ER.
Highlights
Breast cancer is still the most common cancer in women worldwide, affecting one in eight women in high-income countries, and the incidence is further increasing.[1]
ESR1 alterations represent, with approximately 20%, the largest category.[6,8]. These ESR1 point mutations, for instance, are frequently located in the ligand binding domain (LBD) and require the search for new antiestrogenic drugs to overcome this kind of resistance.[9]
It is based on the crystal structure of the ERβ-LBD (PDB entry 2FSZ)[26] cocrystallized with two 4-OHT molecules.[24]
Summary
Breast cancer is still the most common cancer in women worldwide, affecting one in eight women in high-income countries, and the incidence is further increasing.[1] The majority of all types of mammary carcinomas (MCs) are, at least initially, hormone-dependent.[2,3] Endocrine therapy, including aromatase inhibitors or selective estrogen receptor modulators (SERMs)/ selective estrogen receptor downregulators (SERDs), represents an indispensable treatment opportunity. With regard to genomic alterations, endocrine-resistant breast tumors are divided into four groups: (i) tumors bearing estrogen receptor alpha (ERα) gene alterations (ESR1), (ii) tumors harboring lesions in the mitogen-activated protein kinase pathway, (iii) tumors with mutations in the transcriptional factors, and (iv) tumors with undiscovered resistance mechanisms.[6,7] ESR1 alterations represent, with approximately 20%, the largest category.[6,8] These ESR1 point mutations, for instance, are frequently located in the ligand binding domain (LBD) and require the search for new antiestrogenic drugs to overcome this kind of resistance.[9]
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