Screening uncovers diverse PYCR1 inhibitors acting at several sites, including a covalent pocket
- Screening a large chemical biology library and a kinase inhibitor set yielded well over a hundred validated PYCR1 inhibitors across many chemotypes.
- Crystal structures showed most ligands binding outside the catalytic site, revealing several ligandable regions, including a new pocket for covalent targeting of Cys262.
- Another allosteric ligand displaces Gln10 and disrupts NADH binding; kinase-derived hits were mostly mixed-type, giving starting points for probes.
💡 Points Based on the abstract
This is more a ligandability map than a lead list: a hundred-plus hits across chemotypes show where PYCR1 can be drugged, not what to progress. For the Cys262 pocket, kinact/KI and proteome-wide cysteine selectivity are the numbers to see. Kinase-derived hits should be counter-screened against PYCR2/3 and the kinome before anyone calls them probes.