Identification of 3,6-disubstituted dihydropyrones as inhibitors of human lactate dehydrogenase.
A series of 3,6-disubstituted dihydropyrones were identified as inhibitors of human lactate dehydrogenase (LDH)-A. Structure activity relationships were explored and a series of 6,6-spiro analogs led to improvements in LDHA potency (IC50 <350 nM). An X-ray crystal structure of an improved compound bound to human LDHA was obtained and it illustrated additional opportunities to enhance the potency of these compounds, resulting in the identification of 51 (IC50=30 nM).
['Fauber|Benjamin P|BP|', 'Dragovich|Peter S|PS|', 'Chen|Jinhua|J|', 'Corson|Laura B|LB|', 'Ding|Charles Z|CZ|', 'Eigenbrot|Charles|C|', 'Labadie|Sharada|S|', 'Malek|Shiva|S|', 'Peterson|David|D|', 'Purkey|Hans E|HE|', 'Robarge|Kirk|K|', 'Sideris|Steve|S|', 'Ultsch|Mark|M|', 'Wei|BinQing|B|', 'Yen|Ivana|I|', 'Yue|Qin|Q|', 'Zhou|Aihe|A|']
D001665:Binding Sites D018360:Crystallography, X-Ray D004791:Enzyme Inhibitors D006801:Humans D007770:L-Lactate Dehydrogenase D008958:Models, Molecular D015394:Molecular Structure D011753:Pyrones D013329:Structure-Activity Relationship
LDHA X-ray crystal structure Tumor metabolism