Moi Davide, Bonanni Davide, Belluti Silvia, Linciano Pasquale, Citarella Andrea, Franchini Silvia, Sorbi Claudia, Imbriano Carol, Pinzi Luca, Rastelli Giulio
Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125, Modena, Italy.
Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125, Modena, Italy.
Eur J Med Chem. 2023 Nov 15;260:115730. doi: 10.1016/j.ejmech.2023.115730. Epub 2023 Aug 16.
The development of drugs for the treatment of advanced prostate cancer (PCA) remains a challenging task. In this study we have designed, synthesized and tested twenty-nine novel HDAC inhibitors based on three different zinc binding groups (trifluoromethyloxadiazole, hydroxamic acid, and 2-mercaptoacetamide). These warheads were conveniently tethered to variously substituted phenyl linkers and decorated with differently substituted pyrrolo-pyrimidine and purine cap groups. Remarkably, most of the compounds showed nanomolar inhibitory activity against HDAC6. To provide structural insights into the Structure-Activity Relationships (SAR) of the investigated compounds, docking of representative inhibitors and molecular dynamics of HDAC6-inhibitor complexes were performed. Compounds of the trifluoromethyloxadiazole and hydroxamic acid series exhibited promising anti-proliferative activities, HDAC6 targeting in PCA cells, and in vitro tumor selectivity. Representative compounds of the two series were tested for solubility, cell permeability and metabolic stability, demonstrating favorable in vitro drug-like properties. The more interesting compounds were subjected to migration assays, which revealed that compound 13 and, to a lesser extent, compound 15 inhibited the invasive behaviour of androgen-sensitive and -insensitive advanced prostate cancer cells. Compound 13 was profiled against all HDACs and found to inhibit all members of class II HDACs (except for HDAC10) and to be selective with respect to class I and class IV HDACs. Overall, compound 13 combines potent inhibitory activity and class II selectivity with favorable drug-like properties, an excellent anti-proliferative activity and marked anti-migration properties on PCA cells, making it an excellent lead candidate for further optimization.
开发用于治疗晚期前列腺癌（PCA）的药物仍然是一项具有挑战性的任务。在本研究中，我们基于三种不同的锌结合基团（三氟甲基恶二唑、异羟肟酸和2-巯基乙酰胺）设计、合成并测试了29种新型HDAC抑制剂。这些弹头方便地连接到各种取代的苯基连接体上，并用不同取代的吡咯并嘧啶和嘌呤帽基团进行修饰。值得注意的是，大多数化合物对HDAC6表现出纳摩尔抑制活性。为了深入了解所研究化合物的构效关系（SAR），我们进行了代表性抑制剂的对接以及HDAC6-抑制剂复合物的分子动力学研究。三氟甲基恶二唑和异羟肟酸系列的化合物表现出有前景的抗增殖活性、在PCA细胞中靶向HDAC6以及体外肿瘤选择性。对这两个系列的代表性化合物进行了溶解度、细胞通透性和代谢稳定性测试，结果表明它们具有良好的体外类药性质。对更有意义的化合物进行了迁移试验，结果显示化合物13以及在较小程度上化合物15抑制了雄激素敏感和不敏感的晚期前列腺癌细胞的侵袭行为。对化合物13针对所有HDAC进行了分析，发现它抑制II类HDAC的所有成员（HDAC10除外），并且对I类和IV类HDAC具有选择性。总体而言，化合物13结合了强效抑制活性和II类选择性以及良好的类药性质、出色的抗增殖活性和对PCA细胞显著的抗迁移性质，使其成为进一步优化的优秀先导候选物。
