35468-80-5Relevant academic research and scientific papers
Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase
Chen, Jinhua,Corson, Laura B.,DiPasquale, Antonio,Dragovich, Peter S.,Eigenbrot, Charles,Evangelista, Marie,Fauber, Benjamin P.,Hitz, Anna,Hong, Rebecca,Labadie, Sharada S.,Lai, Kwong Wah,Liu, Wenfeng,Ma, Shuguang,Malek, Shiva,O'Brien, Thomas,Pang, Jodie,Peterson, David,Purkey, Hans E.,Robarge, Kirk,Salphati, Laurent,Sampath, Deepak,Sideris, Steven,Ultsch, Mark,Wei, BinQing,Xu, Zijin,Yen, Ivana,Yu, Dong,Yue, Qin,Zhou, Aihe
, (2022/02/02)
Structure-based design was utilized to optimize 6,6-diaryl substituted dihydropyrone and hydroxylactam to obtain inhibitors of lactate dehydrogenase (LDH) with low nanomolar biochemical and single-digit micromolar cellular potencies. Surprisingly the replacement of a phenyl with a pyridyl moiety in the chemical structure revealed a new binding mode for the inhibitors with subtle conformational change of the LDHA active site. This led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.
