血管生成拟态（VM）是恶性黑色素瘤预后不良的一个因素。开发针对黑色素瘤 VM 的脱氧马尿苷合成酶 (DHPS) 抑制剂在临床上至关重要。本研究根据候选结构优化合成了一系列化合物，并通过酶测定和细胞活力抑制筛选鉴定出命中化合物7k。在细胞内部和外部，7k 靶向 DHPS 的能力及其高亲和力都得到了证明。分子动力学和点突变表明DHPS中K329或V129的突变消除了7k的抑制活性。使用 PCR 阵列、固态抗体微阵列和血管生成测定研究了 7k 对黑色素瘤细胞的影响，揭示 DHPS 通过促进 FGFR2 和 c-KIT 表达来调节黑色素瘤 VM。令人惊讶的是，7k 被发现可以抑制斑马鱼中 MC1R 介导的黑色素合成。药代动力学评估证明了 7k 的良好特性，异种移植模型证明了其显着的抗黑色素瘤功效，TGI 达到 73%。这些结果强调了 DHPS 在黑色素瘤 VM 形成中的关键作用，并证实了 7k 作为新型抗黑色素瘤药物的潜力。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Vasculogenic mimicry (VM) contributes factor to the poor prognosis of malignant melanoma. Developing deoxyhypusine synthase (DHPS) inhibitors against melanoma VM is clinically essential. In this study, we optimized and synthesized a series of compounds based on the candidate structure, and the hit compound 7k was identified through enzyme assay and cell viability inhibition screening. Both inside and outside the cell, 7k's ability to target DHPS and its high affinity were demonstrated. Molecular dynamics and point mutation indicated that mutations of K329 or V129 in DHPS abolish 7k's inhibitory activity. Using PCR arrays, solid-state antibody microarrays, and angiogenesis assays investigated 7k's impact on melanoma cells to reveal that DHPS regulates melanoma VM by promoting FGFR2 and c-KIT expression. Surprisingly, 7k was discovered to inhibit MC1R-mediated melanin synthesis in the zebrafish. Pharmacokinetic evaluations demonstrated 7k's favorable properties, and xenograft models evidenced its notable anti-melanoma efficacy, achieving a TGI of 73 %. These results highlighted DHPS as key in melanoma VM formation and confirmed 7k's potential as a novel anti-melanoma agent.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.