Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor
Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor
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DOI：
10.1021/acs.jmedchem.9b01379
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发表时间：
2020-03-26
影响因子：
7.3
通讯作者：
DeVita, Robert J.
中科院分区：
文献类型：
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作者：
Kumar, Kunal;Wang, Peng;DeVita, Robert J.
最近，我们的研究小组发现，通过DYRK1A-NFAT途径，毒鼠碱能够在体外和体内诱导β细胞增殖。由于有害生物碱对其他激酶和中枢神经系统脱靶缺乏选择性，因此我们寻求扩大有害生物碱DYRK1A活性的结构-活性关系，以增强对脱靶的选择性，同时保持人类β细胞增殖活性。我们优化了harm的9- n位置，合成了29个基于harm的类似物。几种新型抑制剂表现出优异的DYRK1A抑制和人β细胞增殖能力。一种优化的DYRK1A抑制剂2-2c被确定为一种新的、有效的体内先导候选药物。2-2c对激酶和中枢神经系统脱靶有更好的选择性，在体内对β细胞的增殖和再生也有较低剂量的效果。总的来说，这些发现表明，与伤害相比，2-2c在治疗糖尿病方面是一种更好的体内先导候选物。
Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.