Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)

Rai, Ganesha; Brimacombe, Kyle R.; Mott, Bryan T.; Urban, Daniel J.; Hu, Xin; Yang, Shyh-Ming; Lee, Tobie D.; Cheff, Dorian M.; Kouznetsova, Jennifer; Benavides, Gloria A.; Pohida, Katie; Kuenstner, Eric J.; Luci, Diane K.; Lukacs, Christine M.; Davies, Douglas R.; Dranow, David M.; Zhu, Hu; Sulikowski, Gary; Moore, William J.; Stott, Gordon M.; Flint, Andrew J.; Hall, Matthew D.; Darley-Usmar, Victor M.; Neckers, Leonard M.; Dang, Chi V.; Waterson, Alex G.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.

doi:10.1021/acs.jmedchem.7b00941

Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)

Journal Article · Wed Nov 08 23:00:00 EST 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b00941· OSTI ID:1439618

Rai, Ganesha ^[1]; Brimacombe, Kyle R. ^[1]; Mott, Bryan T. ^[1]; Urban, Daniel J. ^[1]; Hu, Xin ^[1]; Yang, Shyh-Ming ^[1]; Lee, Tobie D. ^[1]; Cheff, Dorian M. ^[1]; Kouznetsova, Jennifer ^[1]; Benavides, Gloria A. ^[2]; Pohida, Katie ^[1]; Kuenstner, Eric J. ^[1]; Luci, Diane K. ^[1]; Lukacs, Christine M. ^[3]; Davies, Douglas R. ^[3]; Dranow, David M. ^[3]; Zhu, Hu ^[1]; Sulikowski, Gary ^[4]; Moore, William J. ^[5]; Stott, Gordon M. ^[5] more »

National Inst. of Health, Rockville, MD (United States). National Center for Advancing Translational Sciences
Univ. of Alabama, Birmingham, AL (United States)
Beryllium Discovery Corp., Bainbridge Island, WA (United States)
Vanderbilt Univ., Nashville, TN (United States)
Frederick National Lab. for Cancer Research, MD (United States)
National Cancer Inst. (NCI), Bethesda, MD (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States)

We report herein the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug–target residence time was determined via SPR. Analysis of these data suggests that drug–target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Cancer Institute (NCI); National Institutes of Health (NIH); Intramural Research Program, National Center for Advancing Translational Sciences (NCATS)

OSTI ID:: 1439618

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 60; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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