Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase

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.

https://doi.org/10.1016/j.bmcl.2022.128576 

Authors

BinQingWei^a KirkRobarge^a Sharada S.Labadie^a JinhuaChen^b Laura B.Corson^a AntonioDiPasquale^a Peter S.Dragovich^a CharlesEigenbrot^a MarieEvangelista^a Benjamin P.Fauber^a AnnaHitz^a RebeccaHong^a Kwong WahLai^b WenfengLiu^b ShuguangMa^a ShivaMalek^a ThomasO’Brien^a JodiePang^a DavidPeterson^a LaurentSalphati^a DeepakSampath^a StevenSideris^a MarkUltsch^a ZijinXu^b IvanaYen^a DongYu^b QinYue^a AiheZhou^a Hans E.Purkey^a

^a Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

^b WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China

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