Pinzi Luca, Belluti Silvia, Piccinini Isabella, Imbriano Carol, Rastelli Giulio
Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy.
Pharmaceuticals (Basel). 2024 Aug 15;17(8):1072. doi: 10.3390/ph17081072.
Prostate cancer (PCA) is one of the most prevalent types of male cancers. While current treatments for early-stage PCA are available, their efficacy is limited in advanced PCA, mainly due to drug resistance or low efficacy. In this context, novel valuable therapeutic opportunities may arise from the combined inhibition of histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90). These targets are mutually involved in the regulation of several processes in cancer cells, and their inhibition is demonstrated to provide synergistic effects against PCA. On these premises, we performed an extensive in silico virtual screening campaign on commercial compounds in search of dual inhibitors of HDAC6 and Hsp90. In vitro tests against recombinant enzymes and PCA cells with different levels of aggressiveness allowed the identification of a subset of compounds with inhibitory activity against HDAC6 and antiproliferative effects towards LNCaP and PC-3 cells. None of the candidates showed appreciable Hsp90 inhibition. However, the discovered compounds have low molecular weight and a chemical structure similar to that of potent Hsp90 blockers. This provides an opportunity for structural and medicinal chemistry optimization in order to obtain HDAC6/Hsp90 dual modulators with antiproliferative effects against prostate cancer. These findings were discussed in detail in the study.
前列腺癌（PCA）是男性中最常见的癌症类型之一。虽然目前有针对早期PCA的治疗方法，但它们在晚期PCA中的疗效有限，主要是由于耐药性或疗效不佳。在此背景下，联合抑制组蛋白去乙酰化酶6（HDAC6）和热休克蛋白90（Hsp90）可能会带来新的有价值的治疗机会。这些靶点共同参与癌细胞中多个过程的调控，并且已证明抑制它们可对PCA产生协同作用。基于这些前提，我们对商业化合物进行了广泛的计算机虚拟筛选，以寻找HDAC6和Hsp90的双重抑制剂。针对重组酶和具有不同侵袭性水平的PCA细胞进行的体外试验，使得能够鉴定出一组对HDAC6具有抑制活性且对LNCaP和PC-3细胞具有抗增殖作用的化合物。没有一个候选物显示出明显的Hsp90抑制作用。然而，发现的化合物分子量较低，且化学结构与强效Hsp90阻滞剂相似。这为结构和药物化学优化提供了机会，以便获得对前列腺癌具有抗增殖作用的HDAC6/Hsp90双重调节剂。这些发现已在该研究中进行了详细讨论。
