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Publication Abstract from PubMed

Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of NADH as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52) possess desirable attributes for further studying the effect of in vivo LDH inhibition. .

Pyrazole-Based Lactate Dehydrogenase (LDH) Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties.,Rai G, Urban DJ, Mott BT, Hu X, Yang SM, Benavides GA, Johnson MS, Squadrito GL, Brimacombe KR, Lee TD, Cheff DM, Zhu H, Henderson MJ, Pohida K, Sulikowski GA, Dranow DM, Kabir M, Shah P, Padilha E, Tao D, Fang Y, Christov PP, Kim K, Jana S, Muttil P, Anderson T, Kunda NK, Hathaway HJ, Kusewitt DF, Oshima N, Cherukuri M, Davies DR, Norenberg JP, Sklar LA, Moore WJ, Dang CV, Stott GM, Neckers LM, Flint AJ, Usmar VD, Simeonov A, Waterson AG, Jadhav A, Hall MD, Maloney DJ J Med Chem. 2020 Sep 9. doi: 10.1021/acs.jmedchem.0c00916. PMID:32902275^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.