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.
BinQingWeiKirkRobargeSharada S.LabadieJinhuaChenLaura B.CorsonAntonioDiPasqualePeter S.DragovichCharlesEigenbrotMarieEvangelistaBenjamin P.FauberAnnaHitzRebeccaHongKwong WahLaiWenfengLiuShuguangMaShivaMalekThomasO’BrienJodiePangDavidPetersonLaurentSalphatiDeepakSampathStevenSiderisMarkUltschZijinXuIvanaYenDongYuQinYueAiheZhouHans E.Purkey
- 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