Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase. (1st March 2022)

• Record Type: Journal Article
• Authors: Wei, BinQing; Robarge, Kirk; Labadie, Sharada S.; Chen, Jinhua; Corson, Laura B.; DiPasquale, Antonio; Dragovich, Peter S.; Eigenbrot, Charles; Evangelista, Marie; Fauber, Benjamin P.; Hitz, Anna; Hong, Rebecca; Lai, Kwong Wah; Liu, Wenfeng; Ma, Shuguang; Malek, Shiva; O'Brien, Thomas; Pang, Jodie; Peterson, David; Salphati, Laurent; Sampath, Deepak; Sideris, Steven; Ultsch, Mark; Xu, Zijin; Yen, Ivana; Yu, Dong; Yue, Qin; Zhou, Aihe; Purkey, Hans E.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 59(2022)
• Publication Date: 2022-03-01
• Subjects: Lactate dehydrogenase -- Tumor metabolism -- Glycolysis -- X-ray crystal structure -- Structure-based design; LDHA lactate dehydrogenase A -- LDHB lactate dehydrogenase B -- PPB plasma protein binding -- MDCK Madin-Darby canine kidney -- AUC area under the curve -- Vss steady-state volume of distribution -- T1/2 half-life -- Clp plasma clearance -- Cmax maximum concentration -- F oral bioavailability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128576
• Languages: English
• ISSNs: 0960-894X

Abstract

Abstract: 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.