92057-12-0Relevant articles and documents
Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors
Xiang, Qiuping,Luo, Guolong,Zhang, Cheng,Hu, Qingqing,Wang, Chao,Wu, Tianbang,Xu, Hongrui,Hu, Jiankang,Zhuang, Xiaoxi,Zhang, Maofeng,Wu, Shuang,Xu, Jinxin,Zhang, Yan,Liu, Jinsong,Xu, Yong
, (2022/04/07)
TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics “readers” and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 μM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.
COMPOUNDS AND METHODS TO ATTENUATE TUMOR PROGRESSION AND METASTASIS
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Paragraph 0266-0267; 0275-0276, (2020/05/28)
This invention relates to certain compounds or pharmaceutically acceptable salts thereof, and for the use of the compounds to treat cancer. In another aspect, the disclosure relates to a pharmaceutical composition comprising a compound of Formula (1), For
Diarylureas Containing 5-Membered Heterocycles as CB1 Receptor Allosteric Modulators: Design, Synthesis, and Pharmacological Evaluation
Nguyen, Thuy,Gamage, Thomas F.,Decker, Ann M.,German, Nadezhda,Langston, Tiffany L.,Farquhar, Charlotte E.,Kenakin, Terry P.,Wiley, Jenny L.,Thomas, Brian F.,Zhang, Yanan
, p. 518 - 527 (2018/10/02)
Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB1 receptor signaling for therapeutic benefits that may avoid the adverse effects associated with orthosteric ligands. Here we extended our previous structure-activity relationship studies on the diarylurea-based CB1 negative allosteric modulators (NAMs) by introducing five-membered heterocycles to replace the 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of the first generation CB1 allosteric modulators. Many of these compounds had comparable potency to 1 in blocking the CB1 agonist CP55,940 stimulated calcium mobilization and [35S]GTP-γ-S binding. Similar to 1, most compounds showed positive cooperativity by increasing [3H]CP55,940 binding, consistent with the positive allosteric modulator (PAM)-antagonist mechanism. Interestingly, these compounds exhibited differences in ability to increase specific binding of [3H]CP55,940 and decrease binding of the antagonist [3H]SR141716. In saturation binding studies, only increases in [3H]CP55,940 Bmax, but not Kd, were observed, suggesting that these compounds stabilize low affinity receptors into a high affinity state. Among the series, the 2-pyrrolyl analogue (13) exhibited greater potency than 1 in the [35S]GTP-γ-S binding assay and significantly enhanced the maximum binding level in the [3H]CP5,5940 binding assay, indicating greater CB1 receptor affinity and/or cooperativity.
