3ARA

Discovery of Novel Uracil Derivatives as Potent Human dUTPase Inhibitors

Summary for 3ARA

• Entry DOI: 10.2210/pdb3ara/pdb
• Related: 1Q5H 2HQU 3EHW
• Descriptor: Deoxyuridine 5'-triphosphate nucleotidohydrolase, 1-[3-({(2R)-2-[hydroxy(diphenyl)methyl]pyrrolidin-1-yl}sulfonyl)propyl]pyrimidine-2,4(1H,3H)-dione, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: hydrolase, magnesium binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Nucleus . Isoform 3: Mitochondrion : P33316
• Total number of polymer chains: 3
• Total formula weight: 54770.47

Authors

Chong, K.T.,Miyakoshi, H.,Miyahara, S.,Fukuoka, M. (deposition date: 2010-11-25, release date: 2010-12-08, Last modification date: 2024-03-13)

Primary citation

Miyakoshi, H.,Miyahara, S.,Yokogawa, T.,Chong, K.T.,Taguchi, J.,Endoh, K.,Yano, W.,Wakasa, T.,Ueno, H.,Takao, Y.,Nomura, M.,Shuto, S.,Nagasawa, H.,Fukuoka, M.
Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors
J.Med.Chem., 55:2960-2969, 2012

PubMed Abstract: Recently, deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy of 5-fluorouracil-based combination chemotherapy. We have initiated a program to develop potent drug-like dUTPase inhibitors based on structure-activity relationship (SAR) studies of uracil derivatives. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC(50) = 0.15 μM). The X-ray structure of a complex of 16a and human dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a hydrophobic region, respectively, and are stacked on each other. Compounds 12a and 16a markedly enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = 0.27-0.30 μM), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors.

PubMed: 22404301
DOI: 10.1021/jm201627n

Experimental method

X-RAY DIFFRACTION (1.7 Å)