N-Propargylglycine: a unique suicide inhibitor of proline dehydrogenase with anticancer activity and brain-enhancing mitohormesis properties

• DOI: 10.1007/s00726-021-03012-9
• Publication Date: 2021-06-05T06:02:54Z
• Authors: Gary K. Scott; Sophia Mahoney; Madeleine Scott; Ashley Loureiro; Alejandro Lopez-R...; John J. Tanner; Lisa M. Ellerby; Christopher C. Benz
• Keywords: Proline dehydrogenase

Proline dehydrogenase (PRODH) is a mitochondrial inner membrane flavoprotein critical for cancer cell survival under stress conditions and newly recognized as potential target drug development. Reversible (competitive) irreversible (suicide) inhibitors of PRODH have been shown in vivo to inhibit growth with excellent host tolerance. Surprisingly, the suicide inhibitor N-propargylglycine (N-PPG) also induces rapid decay concordant upregulation chaperones (HSP-60, GRP-75) protease YME1L1, signifying activation unfolded protein response (UPRmt) independent anticancer activity. The present study was undertaken address two aims: (i) use overexpressing human cells (ZR-75-1) confirm UPRmt inducing properties N-PPG relative another equipotent inhibitor, thiazolidine-2-carboxylate (T2C); (ii) employ biochemical transcriptomic approaches determine if orally administered can penetrate blood-brain barrier, essential its future brain therapeutic, potentially protect normal tissue by mitohormesis. Oral daily treatments produced dose-dependent decline without detectable impairment mouse health; furthermore, mice repeatedly dosed 50 mg/kg showed increased expression mitohormesis associated protease, YME1L1. Whole transcriptome (RNAseq) analyses these revealed significant gene set enrichment stimulated neural processes (FDR p < 0.05). Given this evidence bioavailability induction, appears be unique among agents should evaluated repurposing pharmaceutical capable mitigating proteotoxic mechanisms driving neurodegenerative disorders.