黑色素瘤是由黑色素细胞癌变而来的皮肤癌症，具有侵袭性强、易转移、预后差等特点1。近年来，黑色素瘤发病率和病死率逐年上升，严重危害人类的生命健康2。脱氧羟腐胺赖氨酸合酶（deoxyhypusine synthase，DHPS）是催化真核细胞翻译起始因子5A（eukaryotic translation initiation factor 5A，eIF5A）羟腐胺化的关键酶，羟腐胺化修饰过程是将亚精胺的4-氨基丁基转移到eIF5A前体的特定赖氨酸上，eIF5A经过修饰后的才具有完整功能，在多种细胞进程中起关键作用3,4。研究发现，DHPS在多种肿瘤中高表达，
经羟腐胺化的eIF5A能促进肿瘤的发展，使用DHPS抑制剂限制DHPS的催化功能可以有效抑制肿瘤细胞的增殖5。
在黑色素瘤中，DHPS除了具有上述功能外，还具有与其他肿瘤不同的作用：DHPS能够抑制黑色素瘤细胞中细胞周期抑制因子p21的表达，这种负调节作用与催化功能无关，仅出现在人黑色素瘤细胞A375和SK-MEL-28细胞系中，被称为“细胞种类特异性”6。此外，DHPS催化抑制剂在黑色素瘤细胞和神经母细胞瘤细胞中对p21表现出相反的调节能力，DHPS催化抑制剂能够抑制黑色素瘤细胞中p21的表达6，却会增加神经母细胞瘤细胞中p21的含量7,8，这也是黑色素瘤细胞与其他肿瘤细胞的不同之处。一直以来对p21的认知是：
p21是肿瘤抑制因子p53的主要效应物，能够抑制细胞周期的进程而发挥抑癌作用9，然而研究表明，p21在肿瘤中是一把双刃剑，在不经p53调控时，具有促癌作用10。在黑色素瘤细胞中，p21的表达与p53含量无关11。p21可以与小眼畸形相关转录因子（microphthalmia-associated transcription factor，MITF）形成正反馈回路，促进黑色素相关蛋白的表达，进而促进黑色素瘤的发展11。
由此可初步推断，针对DHPS开发基因药物、PROTAC药物或分子胶药物与抑制DHPS催化功能的小分子药物作用机制不同，这一点在指导教师的前期研究中也得到证实，针对DHPS靶点的siRNA和DHPS催化功能抑制剂进行基因测序，发现它们对黑色素瘤细胞中癌基因的
影响不同，小分子药物比siRNA更能够有效下调多种癌基因的表达，进一步证实了DHPS催化功能抑制剂的优越性。
针对DHPS催化功能对的抑制剂分两大类，一类是DHPS底物抑制剂，这类小分子化合物是模拟DHPS底物亚精胺的结构，占据DHPS蛋白上亚精胺的结合位点，阻碍4-氨基丁基的转移，从而抑制eIF5A的羟腐胺化12。DHPS底物抑制剂发现早，种类多，以GC7为代表，能够抑制多种癌细胞的增殖13–17。而体内亚精胺的生理功能并不局限于eIF5A的活化，导致亚精胺的作用位点多，如β肾上腺素受体18和线粒体三功能蛋白（mitochondrial trifunctional protein，MTP）19，因此通过模拟亚精胺的结构得到的DHPS底物抑制剂具有多靶点的缺点。目前所有DHPS底物抑制剂中，研究最为深入的GC7具有选择性低、体内活性差的缺点，在异种移植黑色素瘤模型中无肿瘤抑制能力20。
另一类抑制剂为DHPS变构抑制剂，这类抑制剂发现较晚，目前关于变构抑制剂的新化合物的文献仅有三篇。其中两篇是Yuta Tanaka等人于2020年根据高通量筛选发现DHPS变构位点，设计并合成了两类DHPS变构抑制剂，分别是酰胺吲哚类21和二氢噻吩并吡啶类22，这两类化合物与DHPS变构位点结合后，导致NAD（DHPS需要在NAD的参与下才能够进行羟腐胺化修饰）和亚精胺结合位点附近的α螺旋展开，发生空间位置变化的氨基酸残基占据NAD或亚精胺的结合位点，从而抑制DHPS的催化活性，这为开发高选择性的DHPS抑制剂提供了思路，也是开发以DHPS为靶点的抗黑色素瘤药物的出路。但是Yuta Tanaka等人并没有进一步检测这两类化合物的肿瘤抑制能力。第三篇是指导教师于2021年根据DHPS变构位点开发而来的苯基嘧啶类化合物A8m23，并进一步深入研究发现DHPS变构抑制剂与黑色素瘤之间的关系。
指导教师近年来一直从事DHPS变构抑制剂的抗黑色素瘤研究，首次报道了苯基嘧啶类DHPS变构抑制剂，该类化合物结构新颖、选择性高、毒性低。其中化合物A8m23在体内和体外的抗黑色素瘤能力均优于GC7，应用前景广阔，值得深入研究。
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1.与本项目有关的研究积累和已取得的成绩
