4 years ago

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

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

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00941

DOI: 10.1021/acs.jmedchem.7b00941

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.