Open AccessDiscovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
Author(s) -
Ganesha Rai,
Kyle R. Brimacombe,
Bryan T. Mott,
Daniel J. Urban,
Xin Hu,
ShyhMing Yang,
Tobie D. Lee,
Dorian M. Cheff,
Jennifer Kouznetsova,
Gloria A. Benavides,
Katie Pohida,
Eric J. Kuenstner,
Diane K. Luci,
Christine Lukacs,
D.R. Davies,
David M. Dranow,
Hongguang Zhu,
Gary A. Sulikowski,
William Moore,
Gordon M. Stott,
Andrew Flint,
Matthew D. Hall,
Victor DarleyUsmar,
Leonard Μ. Neckers,
Chi V. Dang,
Alex G. Waterson,
Anton Simeonov,
Ajit Jadhav,
David J. Maloney
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.7b00941
Subject(s) - chemistry , lactate dehydrogenase , enzyme , drug discovery , lactate dehydrogenase a , lead compound , cancer cell , biochemistry , glycolysis , dehydrogenase , pyrazole , pharmacology , cancer , in vitro , stereochemistry , biology , genetics
We report 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.