CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Christian Doppler Laboratory for Chemical Epigenetics and Anti infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Nat Chem Biol. 2017 Jul;13(7):771-778. doi: 10.1038/nchembio.2382. Epub 2017 May 22.
Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.
已批准的药物是研究生化途径的宝贵工具，而对这些化合物的进一步表征可能导致单一药物或组合药物的重新定位。在这里，我们描述了一个由 308 种小分子组成的集合，这些小分子代表了所有 FDA 批准的化学实体的结构和分子靶标的多样性。CeMM 独特药物库 (CLOUD) 涵盖了在药理学相关浓度下的前药和活性形式，非常适合组合研究。我们对 CLOUD 药物的成对组合进行了筛选，以检测其对癌细胞活力的损害，并发现了氟他胺和苯茚二酮（PPC）之间的协同相互作用。将这两种药物联合使用可以调节雄激素受体（AR）的稳定性，并使 AR 突变型前列腺癌细胞对氟他胺重新敏感。从机制上讲，我们表明 AR 是 γ-羧化作用的底物，这是一种被 PPC 抑制的翻译后修饰。总的来说，我们的数据表明，PPC 可以被重新用于解决前列腺癌患者对雄激素拮抗剂的耐药性问题。
