The Highly Potent AhR Agonist Picoberin Modulates Hh-Dependent Osteoblast Differentiation

Identification and
analysis of small molecule bioactivity
in target-agnostic
cellular assays and monitoring changes in phenotype followed by identification
of the biological target are a powerful approach for the identification
of novel bioactive chemical matter in particular when the monitored
phenotype is disease-related and physiologically relevant. Profiling
methods that enable the unbiased analysis of compound-perturbed states
can suggest mechanisms of action or even targets for bioactive small
molecules and may yield novel insights into biology. Here we report
the enantioselective synthesis of natural-product-inspired 8-oxotetrahydroprotoberberines
and the identification of Picoberin, a low picomolar inhibitor of
Hedgehog (Hh)-induced osteoblast differentiation. Global transcriptome
and proteome profiling revealed the aryl hydrocarbon receptor (AhR)
as the molecular target of this compound and identified a cross talk
between Hh and AhR signaling during osteoblast differentiation.

在靶标无关（target-agnostic）细胞实验中鉴定并分析小分子生物活性，监测表型变化并确定生物学靶标，是发现新型活性化学物质的有效策略，尤其当所监测的表型与疾病相关且具备生理学相关性时。可对化合物扰动状态进行无偏分析的表征方法，不仅能够揭示生物活性小分子的作用机制乃至其作用靶标，还可为生物学研究提供全新见解。本研究报道了受天然产物启发的8-氧代四氢原小檗碱类化合物的对映选择性合成，并鉴定出Picoberin——一种皮摩尔级强效抑制刺猬（Hedgehog, Hh）通路诱导的成骨细胞分化的抑制剂。通过全局转录组（global transcriptome）与蛋白质组（proteome）表征分析，本研究揭示芳香烃受体（aryl hydrocarbon receptor, AhR）为该化合物的分子靶标，并阐明了成骨细胞分化过程中Hh与AhR信号通路之间的交叉串扰。