Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France.
Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), 50018, Zaragoza, Spain.
Sci Rep. 2024 Nov 27;14(1):29515. doi: 10.1038/s41598-024-79340-z.
Pancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel. To address this, we have performed a high-throughput screening of 10,000 compounds from the HitFinder Chemical Library, and identified AJO14 as a lead compound that binds to NUPR1, without having favorable affinity towards hERG. AJO14 induced cell death through apoptosis, necroptosis, and parthanatos (induced by the poly-ADP ribose polymerase (PARP) overactivation), driven by mitochondrial catastrophe and decreased ATP production. This process seemed to be mediated by the hyperPARylation (an excessive modification of proteins by PARP, leading to cellular dysfunction), as it could be reversed by Olaparib, a PARP inhibitor. In xenografted mice, AJO14 demonstrated a dose-dependent tumor reduction activity. Furthermore, we attempted to improve the anti-cancer properties of AJO14 by molecular modification of the lead compound. Among the 51 candidates obtained and tested, 8 compounds exhibited a significant increase in efficacy and have been retained for further studies, especially LZX-2-73. These AJO14-derived compounds offer potent NUPR1 inhibition for pancreatic cancer treatment, without cardiotoxicity concerns.
胰腺癌致死率高，治疗选择有限。我们的团队此前开发了 ZZW-115，这是一种有前途的药物候选物，针对核蛋白 1（NUPR1），它参与胰腺癌的发展和进展。然而，由于其与人类 Ether-à-go-go-Related Gene（hERG）钾通道的相互作用导致潜在的心脏毒性，ZZW-115 的临床转化受到阻碍。为了解决这个问题，我们对来自 HitFinder 化学文库的 10000 种化合物进行了高通量筛选，鉴定出 AJO14 是一种与 NUPR1 结合的先导化合物，对 hERG 没有亲和力。AJO14 通过细胞凋亡、坏死和 parthanatos（由多聚 ADP 核糖聚合酶 (PARP) 过度激活引起）诱导细胞死亡，这是由线粒体灾难和减少的 ATP 产生驱动的。这个过程似乎是由 hyperPARylation（PARP 对蛋白质的过度修饰，导致细胞功能障碍）介导的，因为它可以被 PARP 抑制剂 Olaparib 逆转。在异种移植小鼠中，AJO14 表现出剂量依赖性的肿瘤减少活性。此外，我们试图通过对先导化合物进行分子修饰来提高 AJO14 的抗癌特性。在获得并测试的 51 个候选物中，有 8 个化合物表现出显著增强的疗效，已被保留用于进一步研究，特别是 LZX-2-73。这些源自 AJO14 的化合物为胰腺癌治疗提供了有效的 NUPR1 抑制作用，而没有心脏毒性问题。
