Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation.
Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation.
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DOI：
10.1021/acs.jmedchem.8b00658
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发表时间：
2018-09-13
影响因子：
7.3
通讯作者：
DeVita RJ
中科院分区：
文献类型：
--
作者：
Kumar K;Wang P;Sanchez R;Swartz EA;Stewart AF;DeVita RJ
DYRK 1A已被认为是包括神经系统疾病和肿瘤学在内的各种治疗领域的重要药物靶标。DYRK 1A最近被证明参与调节人类β细胞增殖的途径，从而使其成为1型和2型糖尿病的潜在治疗靶点。我们的小组，使用高通量表型筛选，鉴定了能够在体外和体内诱导β细胞增殖的去氢骆驼蓬碱。由于去氢骆驼蓬碱具有次优的激酶选择性，我们试图扩大去氢骆驼蓬碱的DYRK 1A活性的结构-活性关系，以提高选择性，同时保留人β细胞增殖能力。我们对去氢骆驼蓬碱的1-位进行了优化，合成了15个去氢骆驼蓬碱类似物。六种化合物显示出优异的DYRK 1A抑制作用，IC 50在49.5-264 nM范围内。两种化合物2-2和2-8在3-30 μM剂量下表现出优异的人β细胞增殖，并且化合物2-2与骆驼蓬碱相比显示出改善的激酶选择性。
DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders and oncology. DYRK1A has more recently been shown to be involved in pathways regulating human β-cell proliferation, thus making it a potential therapeutic target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput phenotypic screen, identified harmine that is able to induce β-cell proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand structure−activity relationships for harmine’s DYRK1A activity, to enhance selectivity, while retaining human β-cell proliferation capability. We carried out the optimization of the 1-position of harmine and synthesized 15 harmine analogues. Six compounds showed excellent DYRK1A inhibition with IC50 in the range of 49.5–264 nM. Two compounds, 2–2 and 2–8, exhibited excellent human β-cell proliferation at doses of 3–30 μM, and compound 2–2 showed improved kinase selectivity as compared to harmine.
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