Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.
Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.
复制标题
作为共价 PPARG 反向激动剂的口服生物可利用的 4-氯-6-氟间苯二甲酰胺的发现和表征。
DOI：
10.1016/j.bmc.2022.117130
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发表时间：
2023
影响因子：
3.5
通讯作者：
Jerchel-Fu
中科院分区：
文献类型：
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作者：
Orsi,DouglasL;Ferrara,StevenJ;Siegel,Stephan;Friberg,Anders;Bouché,Léa;Pook,Elisabeth;Lienau,Philip;Bluck,JosephP;Lemke,ChristopherT;Akcay,Gizem;Stellfeld,Timo;Meyer,Hanna;Pütter,Vera;Holton,SimonJ;Korr,Daniel;Jerchel-Fu
PPAR γ（PPARG）是一种配体激活的转录因子，其调节参与炎症、骨生物学、脂质稳态的基因，以及脂肪生成的主要调节因子和管腔膀胱癌的潜在谱系驱动因子。虽然PPARG激动剂导致典型靶基因的转录激活，但反向激动剂通过诱导导致典型靶基因表达抑制的转录抑制复合物而具有相反的作用。虽然许多激动剂已被描述和临床测试，反向激动剂提供了一个未充分探索的途径来调节PPARG生物体内。目前的反向激动剂缺乏体内特性;在此，我们描述了一系列口服生物可利用的4-氯-6-氟代乙酰胺作为共价PPARG反向激动剂BAY-5516、BAY-5094和BAY-9683的发现和表征。这一系列的结构研究揭示了不同的前和后共价结合位置，这导致了这样的假设，即前共价构象中的相互作用主要负责驱动亲和力，而后共价构象中的相互作用更负责通过增强PPARG与其辅阻遏物的相互作用来实现细胞功能效应。需要同时优化两个不同的状态可能部分解释了观察到的陡峭的SAR。在亚家族中实现了对相关核受体的精细选择性，部分原因是除了通过共价结合至独特定位在PPARG LBD内的反应性半胱氨酸获得的特异性之外，通过SNAr机制具有低反应性的共价弹头。BAY-5516、BAY-5094和BAY-9683导致体内PPARG靶基因表达的药效学调节，与已知的反向激动剂SR 10221相当，并且代表了未来体内研究的新工具，以探索其用于治疗过度活化的PPARG疾病（包括腔膀胱癌和其他疾病）的潜在效用。
PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well as a master regulator of adipogenesis and a potential lineage driver of luminal bladder cancer. While PPARG agonists lead to transcriptional activation of canonical target genes, inverse agonists have the opposite effect through inducing a transcriptionally repressive complex leading to repression of canonical target gene expression. While many agonists have been described and tested clinically, inverse agonists offer an underexplored avenue to modulate PPARG biologyin vivo. Current inverse agonists lack favorablein vivoproperties; herein we describe the discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists, BAY-5516, BAY-5094, and BAY-9683. Structural studies of this series revealed distinct pre- and post-covalent binding positions, which led to the hypothesis that interactions in the pre-covalent conformation are primarily responsible for driving affinity, while interactions in the post-covalent conformation are more responsible for cellular functional effects by enhancing PPARG interactions with its corepressors. The need to simultaneously optimize for two distinct states may partially explain the steep SAR observed. Exquisite selectivity was achieved over related nuclear receptors in the subfamily due in part to a covalent warhead with low reactivity through an SNAr mechanism in addition to the specificity gained through covalent binding to a reactive cysteine uniquely positioned within the PPARG LBD. BAY-5516, BAY-5094, and BAY-9683 lead to pharmacodynamic regulation of PPARG target gene expressionin vivocomparable to known inverse agonist SR10221 and represent new tools for futurein vivostudies to explore their potential utility for treatment of disorders of hyperactivated PPARG including luminal bladder cancer and other disorders.