Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069.
Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069.
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DOI：
10.1021/acs.jmedchem.2c01379
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发表时间：
2022-11-10
影响因子：
7.3
通讯作者：
Goldstein, Jonathan T.
中科院分区：
文献类型：
--
作者：
Orsi, Douglas L.;Pook, Elisabeth;Braeuer, Nico;Friberg, Anders;Lienau, Philip;Lemke, Christopher T.;Stellfeld, Timo;Bruggemeier, Ulf;Putter, Vera;Meyer, Hanna;Baco, Maria;Tang, Stephanie;Cherniack, Andrew D.;Westlake, Lindsay;Bender, Samantha A.;Kocak, Mustafa;Strathdee, Craig A.;Meyerson, Matthew;Eis, Knut;Goldstein, Jonathan T.
配体激活的核受体过氧化物酶体增殖物激活受体-γ（PPARG或PPARγ）代表了新一代癌症治疗的潜在靶标，特别是在肌肉浸润性管腔膀胱癌中，其中PPARγ是关键的谱系驱动因素。在这里，我们公开了一系列的氯硝基芳烃共价反向激动剂的发现，利用苯并恶唑核心，以改善与辅阻遏物NCOR 1和NCOR 2的相互作用。用这些化合物对敏感细胞系进行体外处理，导致对PPARγ靶基因的稳健调节和抗增殖作用。尽管它们的物理化学性质不完善，但这些化合物在体内表现出适度的药效学靶向调节。BAY-4931和BAY-0069的体外效力和功效与先前描述的PPARγ反向激动剂相比的改善表明，这些化合物是用于探测PPARγ反向激动作用的体外生物学的新工具。
The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARγ inverse-agonism.
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影响因子：
7.7
作者：
Halstead AM;Kapadia CD;Bolzenius J;Chu CE;Schriefer A;Wartman LD;Bowman GR;Arora VK
通讯作者：
Arora VK
影响因子：
11.2
作者：
Goldstein JT;Berger AC;Shih J;Duke FF;Furst L;Kwiatkowski DJ;Cherniack AD;Meyerson M;Strathdee CA
通讯作者：
Strathdee CA
影响因子：
16.6
作者：
Marciano, David P.;Kuruvilla, Dana S.;Boregowda, Siddaraju V.;Asteian, Alice;Hughes, Travis S.;Garcia-Ordonez, Ruben;Corzo, Cesar A.;Khan, Tanya M.;Novick, Scott J.;Park, HaJeung;Kojetin, Douglas J.;Phinney, Donald G.;Bruning, John B.;Kamenecka, Theodore M.;Griffin, Patrick R.
通讯作者：
Griffin, Patrick R.
影响因子：
3.9
作者：
Kalvass, J. Cory;Phipps, Colin;Fischer, Volker
通讯作者：
Fischer, Volker
影响因子：
46.9
作者：
Yu C;Mannan AM;Yvone GM;Ross KN;Zhang YL;Marton MA;Taylor BR;Crenshaw A;Gould JZ;Tamayo P;Weir BA;Tsherniak A;Wong B;Garraway LA;Shamji AF;Palmer MA;Foley MA;Winckler W;Schreiber SL;Kung AL;Golub TR
通讯作者：
Golub TR