Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Culture West Road, Jinan 250012, PR China.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bioorg Med Chem Lett. 2019 May 1;29(9):1060-1064. doi: 10.1016/j.bmcl.2019.03.005. Epub 2019 Mar 5.
Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton's tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19'c, 21c and 21'c showed potent effect in MCL cells with IC values lower than 1 μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.
套细胞淋巴瘤（MCL）的特征是易位 t（11；14）（q13；q32），导致 cyclin-D1 的过表达。MCL 的进展是多靶点和多环节调节的相互作用。已经证明 Bruton 酪氨酸激酶（BTK）在 MCL 中通常过表达，这使其成为 MCL 靶向治疗的重点。不可逆抑制剂通常具有很强的效力、快速的抑制作用和较长的药物作用持续时间。在此基础上，通过基于先导化合物伊布替尼（IBN）的开环策略进行了结构修饰，得到了一系列吡唑衍生物。化合物 19c、19'c、21c 和 21'c 在 MCL 细胞中表现出很强的作用，IC 值低于 1µM，与 IBN 相比，抗增殖活性增加了 3-28 倍以上。
