8TCY

Structure of PYCR1 complexed with 7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

Summary for 8TCY

• Entry DOI: 10.2210/pdb8tcy/pdb
• Descriptor: Pyrroline-5-carboxylate reductase 1, mitochondrial, 7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, SULFATE ION, ... (5 entities in total)
• Functional Keywords: amino-acid biosynthesis, oxidoreductase, proline biosynthesis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 168571.59

Authors

Tanner, J.J.,Meeks, K.R. (deposition date: 2023-07-02, release date: 2024-03-06, Last modification date: 2024-03-20)

Primary citation

Meeks, K.R.,Ji, J.,Protopopov, M.V.,Tarkhanova, O.O.,Moroz, Y.S.,Tanner, J.J.
Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography.
J.Chem.Inf.Model., 64:1704-1718, 2024

PubMed Abstract: The proline biosynthetic enzyme Δ-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 inhibition of PYCR1 in kinetic assays, and one has lower apparent IC than the current best proline analog inhibitor. These results show proof-of-concept for our inhibitor discovery approach and provide a basis for fragment-to-lead optimization.

PubMed: 38411104
DOI: 10.1021/acs.jcim.3c01879

Experimental method

X-RAY DIFFRACTION (1.95 Å)