鉴定2-苯并恶唑-2-基苯酚骨架作为JMJD3抑制的新活性分子
Identification of the 2-Benzoxazol-2-yl-phenol Scaffold as New Hit for JMJD3 Inhibition.
作者信息
Giordano Assunta, Forte Giovanni, Terracciano Stefania, Russo Alessandra, Sala Marina, Scala Maria C, Johansson Catrine, Oppermann Udo, Riccio Raffaele, Bruno Ines, Di Micco Simone
机构信息
Institute of Biomolecular Chemistry (ICB), Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, I-80078 Pozzuoli, Napoli, Italy.
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, I-84084 Fisciano, Salerno, Italy.
出版信息
ACS Med Chem Lett. 2019 Feb 25;10(4):601-605. doi: 10.1021/acsmedchemlett.8b00589. eCollection 2019 Apr 11.
Abstract
JMJD3 is a member of the KDM6 subfamily and catalyzes the demethylation of lysine 27 on histone H3 (H3K27). This protein was identified as a useful tool in understanding the role of epigenetics in inflammatory conditions and in cancer as well. Guided by a virtual fragment screening approach, we identified the benzoxazole scaffold as a new hit suitable for the development of tighter JMJD3 inhibitors. Compounds were synthesized by a microwave-assisted one-pot reaction under catalyst and solvent-free conditions. Among these, compound presented the highest inhibitory activity (IC = 1.22 ± 0.22 μM) in accordance with molecular modeling calculations. Moreover, induced the cycle arrest in S-phase on A375 melanoma cells.
摘要
JMJD3是KDM6亚家族的成员，可催化组蛋白H3上赖氨酸27（H3K27）的去甲基化。该蛋白被认为是理解表观遗传学在炎症和癌症中作用的有用工具。在虚拟片段筛选方法的指导下，我们确定苯并恶唑支架是适合开发更紧密JMJD3抑制剂的新活性成分。化合物通过微波辅助的一锅反应在无催化剂和无溶剂条件下合成。其中，根据分子模拟计算，化合物表现出最高的抑制活性（IC = 1.22±0.22μM）。此外，在A375黑色素瘤细胞上诱导S期细胞周期停滞。
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