Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, Glasgow G1 1XL, United Kingdom.
H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2626-2631. doi: 10.1016/j.bmcl.2019.07.047. Epub 2019 Jul 25.
Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC = 8.8 µM) and pathway relevant effects in cell-based assays.
吡咯啉-5-羧酸还原酶 1 (PYCR1) 是脯氨酸生物合成中涉及的最后一种酶，已在各种形式的癌症中发现其上调。由于脯氨酸在维持细胞氧化还原平衡和防止细胞凋亡中的作用，PYCR1 正成为一个有吸引力的肿瘤学靶点。先前的 PYCR1 敲除研究导致肿瘤生长减少。因此，PYCR1 的小分子抑制剂可能为癌症治疗带来新方法，有针对性的筛选工作发现帕吉林是一种类似片段的有效化合物。我们报告了源自帕吉林的作为 PYCR1 抑制剂的第一个工具化合物的设计和合成，这些化合物被评估以评估它们抑制脯氨酸产生的能力。结构活性研究揭示了活性的关键决定因素，最有效的化合物 (4) 在体外酶 (IC=8.8µM) 和基于细胞的测定中具有相关途径的效应中表现出改善的活性。
