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

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.

doi:10.1016/j.bmcl.2022.128576

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

Journal Article · Wed Jan 19 00:00:00 EST 2022 · Bioorganic and Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2022.128576· OSTI ID:1981547

Wei, BinQing ^[1]; Robarge, Kirk ^[1]; Labadie, Sharada S. ^[1]; Chen, Jinhua ^[2]; Corson, Laura B. ^[1]; DiPasquale, Antonio ^[1]; Dragovich, Peter S. ^[1]; Eigenbrot, Charles ^[1]; Evangelista, Marie ^[1]; Fauber, Benjamin P. ^[1]; Hitz, Anna ^[1]; Hong, Rebecca ^[1]; Lai, Kwong Wah ^[2]; Liu, Wenfeng ^[2]; Ma, Shuguang ^[1]; Malek, Shiva ^[1]; O'Brien, Thomas ^[1]; Pang, Jodie ^[1]; Peterson, David ^[1]; Salphati, Laurent ^[1] more »

Genentech, San Francisco, CA (United States)
WuXi AppTec, Shanghai (China)

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. Finally, this led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

OSTI ID:: 1981547

Alternate ID(s):: OSTI ID: 1862518

Journal Information:: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: C Vol. 59; ISSN 0960-894X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (14)

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
Glycolysis
Lactate dehydrogenase
Structure-based design
Tumor metabolism
X-ray crystal structure

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

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References (14)

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