CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States.
J Med Chem. 2021 Jul 8;64(13):9330-9353. doi: 10.1021/acs.jmedchem.1c00555. Epub 2021 Jun 28.
Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of -carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our -carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.
由于配体结合域结构高度相似，选择性激动雌激素受体（ER）亚型 ERα 和 ERβ 一直难以实现。多项研究致力于使用经典有机支架来模拟 17β-雌二醇的几何形状，以设计 ERβ 选择性激动剂，其中一些已经进入临床开发的各个阶段。碳硼烷支架具有许多独特的优势，包括可能产生新的配体/受体相互作用，但仍相对未被探索。我们合成了一系列 -碳硼烷雌激素受体激动剂，揭示了 ERβ 选择性的结构-活性关系。我们报告了具有低纳摩尔效力的 ERβ 激动剂，对 ERβ 的选择性比 ERα 高 200 多倍，对其他核受体的脱靶活性有限，并且只有在非常高的微摩尔浓度下才会稀疏地抑制 CYP450。我们的 -碳硼烷 ERβ 选择性激动剂的药理学特性与临床开发的 ERβ 激动剂相当，并支持进一步评估基于碳硼烷的选择性雌激素受体调节剂。
