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

Autor: Wei B; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Wei.BinQing@gene.com., Robarge K; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Labadie SS; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Chen J; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China., Corson LB; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., DiPasquale A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Dragovich PS; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Eigenbrot C; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Evangelista M; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Fauber BP; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Hitz A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Hong R; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Lai KW; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China., Liu W; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China., Ma S; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Malek S; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., O'Brien T; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Pang J; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Peterson D; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Salphati L; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Sampath D; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Sideris S; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Ultsch M; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Xu Z; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China., Yen I; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Yu D; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China., Yue Q; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Zhou A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Purkey HE; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: Purkey.Hans@gene.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Mar 01; Vol. 59, pp. 128576. Date of Electronic Publication: 2022 Jan 19.
DOI: 10.1016/j.bmcl.2022.128576
Abstrakt: 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.
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Databáze: MEDLINE
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