Skip to main content

Sulikowski Lab

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

AUTHORS

Rai GGanesha , Brimacombe KR Kyle R , Mott BT Bryan T , Urban DJ Daniel J , Hu X Xin , Yang SM Shyh-Ming , Lee TD Tobie D , Cheff DM Dorian M , Kouznetsova J Jennifer , Benavides GA Gloria A , Pohida K Katie , Kuenstner EJ Eric J , Luci DK Diane K , Lukacs CM Christine M , Davies DR Douglas R , Dranow DM David M , Zhu H Hu , Sulikowski G Gary , Moore WJ William J , Stott GM Gordon M , Flint AJ Andrew J , Hall MD Matthew D , Darley-Usmar VM Victor M , Neckers LM Leonard M , Dang CV Chi V , Waterson AG Alex G , Simeonov A Anton , Jadhav A Ajit , Maloney DJ David J . Journal of medicinal chemistry. 2017 11 22; 60(22). 9184-9204

ABSTRACT

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.

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.