TY - JOUR
T1 - Development of pathway-oriented screening to identify compounds to control 2-methylglyoxal metabolism in tumor cells
AU - Yanagi, Kouichi
AU - Komatsu, Toru
AU - Fujikawa, Yuuta
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Nagano, Tetsuo
AU - Ueno, Tasuku
AU - Hanaoka, Kenjiro
AU - Urano, Yasuteru
N1 - Funding Information:
This work was financially supported by MEXT (15H05371, 18H04538, 19H02846, 20H04694, 21A303, and 22H02217 to T.K.), JST (PRESTO (13414915), PRESTO Network (17949814), CREST (19204926), and START (20353017) to T.K.), and AMED (FORCE (22581634), P-CREATE (22ama221213h0001 and 22ama221401h0001) to T.K.). T.K. received support from the Naito Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Chugai Foundation for Innovative Drug Discovery Science, and the MSD Life Science Foundation. The inhibitor screening project was supported by the Platform Project for Supporting Drug Discovery and Life Science Research from AMED under Grant Number JP21am0101086 (support number 1637). We thank Mr. Hosei Takai for the assistance in the production and purification of recombinant GSTP1-1.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Controlling tumor-specific alterations in metabolic pathways is a useful strategy for treating tumors. The glyoxalase pathway, which metabolizes the toxic electrophile 2-methylglyoxal (MG), is thought to contribute to tumor pathology. We developed a live cell-based high-throughput screening system that monitors the metabolism of MG to generate d-lactate by glyoxalase I and II (GLO1 and GLO2). It utilizes an extracellular coupled assay that uses d-lactate to generate NAD(P)H, which is detected by a selective fluorogenic probe designed to respond exclusively to extracellular NAD(P)H. This metabolic pathway-oriented screening is able to identify compounds that control MG metabolism in live cells, and we have discovered compounds that can directly or indirectly inhibit glyoxalase activities in small cell lung carcinoma cells.
AB - Controlling tumor-specific alterations in metabolic pathways is a useful strategy for treating tumors. The glyoxalase pathway, which metabolizes the toxic electrophile 2-methylglyoxal (MG), is thought to contribute to tumor pathology. We developed a live cell-based high-throughput screening system that monitors the metabolism of MG to generate d-lactate by glyoxalase I and II (GLO1 and GLO2). It utilizes an extracellular coupled assay that uses d-lactate to generate NAD(P)H, which is detected by a selective fluorogenic probe designed to respond exclusively to extracellular NAD(P)H. This metabolic pathway-oriented screening is able to identify compounds that control MG metabolism in live cells, and we have discovered compounds that can directly or indirectly inhibit glyoxalase activities in small cell lung carcinoma cells.
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U2 - 10.1038/s42004-023-00864-y
DO - 10.1038/s42004-023-00864-y
M3 - Article
AN - SCOPUS:85153187085
SN - 2399-3669
VL - 6
JO - Communications Chemistry
JF - Communications Chemistry
IS - 1
M1 - 68
ER -