Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography.

ABSTRACT: The proline biosynthetic enzyme Δ¹-pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) is one of the most consistently upregulated enzymes across multiple cancer types and central to the metabolic rewiring of cancer cells. Herein, we describe a fragment-based, structure-first approach to the discovery of PYCR1 inhibitors. Thirty-seven fragment-like carboxylic acids in the molecular weight range of 143-289 Da were selected from docking and then screened using X-ray crystallography as the primary assay. Strong electron density was observed for eight compounds, corresponding to a crystallographic hit rate of 22%. The fragments are novel compared to existing proline analog inhibitors in that they block both the P5C substrate pocket and the NAD(P)H binding site. Four hits showed inhibi

SUBMITTER: Meeks KR 

PROVIDER: S-EPMC11058006 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature