Adeluola Adeoluwa A, Radomska Hanna S, Wilson Tyler A, Kulp Samuel K, Kabat Alyssa, Helms Timothy H, Mayo Abigail K, Montgomery Emma J, Thomas Justin, Marcho Lynn M, Costa Travis, Fukuda Mayu, Kang Diana D, Vibhute Sandip, Wang Dasheng, Bennett Chad E, Coss Christopher C
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio.
Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
J Pharmacol Exp Ther. 2025 Jan;392(1):100001. doi: 10.1124/jpet.123.001874. Epub 2024 Nov 22.
Estrogen receptors (ERs) are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of ERβ is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating ERα is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine ERs. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single-dose intravenous and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK-293 cells expressing murine ERs revealed species-specific differences in the ER subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. SIGNIFICANCE STATEMENT: This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors (ERs), revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse ortholog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.
雌激素受体（ERs）是治疗激素紊乱和雌激素依赖性恶性肿瘤的重要药理学靶点。据推测，选择性激活ERβ可带来治疗益处，同时降低与ERα活性相关的不良雌激素副作用风险。然而，由于受体亚型之间高度的序列和结构同源性，在不激活ERα的情况下激活ERβ具有挑战性。我们使用无细胞结合试验评估了母体化合物OSU-ERβ-12的结构修饰对受体亚型结合选择性的影响。通过在过表达人或鼠ERs的HEK-293细胞中的反式激活来评估功能选择性。在雌激素缺乏的雌性小鼠口服给药后，通过类似物的子宫营养作用来检查体内选择性。此外，我们评估了单剂量静脉内和口服给药后类似物的体内药代动力学。关于选择性，一种单一化合物对人ERβ表现出比OSU-ERβ-12更高的功能选择性。然而，与间碳硼烷系列中的其他化合物一样，其较差的体内药代动力学限制了其进一步开发的适用性。令人惊讶的是，与它们的药代动力学和体外人类活性数据不一致的是，大多数类似物在雌激素缺乏的雌性小鼠中强烈诱导子宫营养作用。对表达鼠ERs的HEK-293细胞中活性的进一步研究揭示了这些类似物在ER亚型选择性方面的种属特异性差异。我们的研究结果突出了种属特异性受体药理学及其在临床前物种中表征开发性治疗药物时所带来的挑战。意义声明：本研究调查了靶向雌激素受体（ERs）的对位和间位取代碳硼烷类似物，揭示了碳硼烷类似物对人ERβ的选择性高于小鼠同源物。这些发现揭示了在药物开发中使用临床前物种预测人类药理学的复杂性。该报告还为优化和完善碳硼烷类似物作为雌激素相关疾病状态的潜在治疗药物提供了见解。
