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 (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays.

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Keywords Fragment-based drug discovery, Inhibitor, Oncology, Proline modulation, Tool compound
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Journal Bioorganic and Medicinal Chemistry Letters
Milne, K. (Kirsty), Sun, J. (Jianhui), Zaal, E.A. (Esther A.), Mowat, J. (Jenna), Celie, P.H, Fish, A, … Agami, R. (2019). A fragment-like approach to PYCR1 inhibition. Bioorganic and Medicinal Chemistry Letters. doi:10.1016/j.bmcl.2019.07.047