9-Deazaadenosine directly binds PYCR1 and inhibits cancer cell proliferation through disruption of NAD+ metabolism.

Cancer cells exhibit abnormal proliferation and dysregulated cell cycle checkpoints. Therefore, discovering cell cycle inhibitors is a promising strategy for cancer treatment. The pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme that controls proline metabolism by regulating the conversion of pyrroline-5-carboxylate to proline. PYCR1 is highly expressed in various cancers, including colon cancer. In this study, we discovered a novel role of 9-deazaadenosine (9-DAA) as a cell cycle inhibitor and demonstrated that this compound directly binds to PYCR1. Our results suggest that the inhibitory effects of 9-DAA are due to nicotinamide adenine dinucleotide. We further demonstrated that PYCR1 was elevated under hypoxia and in 3D spheroids in colon cancer and that 9-DAA effectively inhibited cancer progression under cancer-mimicking conditions and in vivo.