ArticleJournal of medicinal chemistry2017
Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).
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Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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82citing papers in PubMed
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82 citing papers in PubMed, 149 citations in OpenAlex.
- Multiscale cross modal fusion and cascaded signal propagation for drug target interaction prediction.iScience · 2026Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- MAGC-DTI: modality-shared space and adaptive gated interactive cross-attention for drug-target interaction prediction.Scientific reports · 2026Article
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review).International journal of molecular medicine · 2026Review
- Development of Biphenyl-Substituted Uracil-Based Hydroxamic Acids (UBHAs) as Potent HDAC Inhibitors with Pro-Apoptotic Activity in Leukemia and Prostate Cancer Cells.Journal of medicinal chemistry · 2026Article
- Lactate metabolic reprogramming and lactylation modification: molecular mechanisms reshaping the tumor immunosuppressive microenvironment.Cell & bioscience · 2026Review
- SLC2A3-Mediated Lactate Metabolism Promotes Lung Cancer Bone Metastasis by Modulating P53 Lactylation and Immune Evasion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Metabolomic and transcriptomic analyses identify metabolic alterations and immune suppression in ovarian cancer.Scientific reports · 2026Article
- Lactylation in cancer: molecular mechanisms and advances in clinical study.Molecular cancer · 2026Review
- Deploying the high-throughput virtual screening (HTVS) approach for the identification of new lactate dehydrogenase (LDH) inhibitors with anticancer assets.Scientific reports · 2026Article
- WDGBANDTI: A Deep Graph Convolutional Network-Based Bilinear Attention Network for Drug-Target Interaction Prediction with Domain Adaptation.Interdisciplinary sciences, computational life sciences · 2025Article
- AI-identified CD133-targeting natural compounds demonstrate differential anti-tumor effects and mechanisms in pan-cancer models.EMBO molecular medicine · 2025Article
- Lactylation in cancer: Advances and opportunities for treatment resistance.Clinical and translational medicine · 2025Review
- Deciphering enemy tactics - the narrow path to an optimal anti-cancer strategy targeting the Warburg effect.Pharmacological reports : PR · 2025Review
- Metabolism, a Blossoming Target for Small-Molecule Anticancer Drugs.Molecules (Basel, Switzerland) · 2025Review
- Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.Journal of biomedical science · 2025Review
- Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small-Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment.Journal of the American Society of Nephrology : JASN · 2025Article
- Design and screening of novel molecular compounds targeting lactate dehydrogenase of Babesia microti.Parasites & vectors · 2025Article
- Lactate and lactylation in cancer.Signal transduction and targeted therapy · 2025Review
22 more citing papers are in PubMed but not listed here.
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Authors and funding
29 authors at 7 institutions in 1 country.
Ganesha RaiNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Kyle R BrimacombeNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Bryan T MottNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Daniel J UrbanNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Xin HuNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Shyh-Ming YangNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Tobie D LeeNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Dorian M CheffNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Jennifer KouznetsovaNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Gloria A BenavidesMitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
Katie PohidaNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Eric J KuenstnerNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Diane K LuciNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Christine M LukacsBeryllium Discovery Corp. , 7869 Day Road West, Bainbridge Island, Washington 98110, United States.
Douglas R DaviesBeryllium Discovery Corp. , 7869 Day Road West, Bainbridge Island, Washington 98110, United States.
David M DranowBeryllium Discovery Corp. , 7869 Day Road West, Bainbridge Island, Washington 98110, United States.
Hu ZhuNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Gary SulikowskiVanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
William J MooreNExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
Gordon M StottNExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
Andrew J FlintNExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.
Matthew D HallNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.ORCID 0000-0002-5073-442X
Victor M Darley-UsmarMitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
Leonard M NeckersUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute , 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
Chi V DangAbramson Cancer Center, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania , Philadephia, Pennsylvania 19104, United States.
Alex G WatersonVanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
Anton SimeonovNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
Ajit JadhavNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
David J MaloneyNational Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.ORCID 0000-0002-5607-4178
National Institutes of Health · USBeryllium (United States) · USLeidos (United States) · USUniversity of Alabama at Birmingham · USVanderbilt University · USCancer Research Institute · USNational Cancer Institute · US
Funding
Tumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Luis J Montaner · 1985 to 2026
$75.9MRole of fumarate hydratase loss in development of HLRCC hereditary kidney cancerZIABC010683 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NECKERS, LEONARD · 2009 to 2024
$8.6MC-MYC TARGETS IN THE PATHOGENESIS OF HUMAN CANCERSR01CA057341 · NCI · WISTAR INSTITUTE · PI DANG, CHI V. · 1992 to 2021
$8.3MMYC--TRANSCRIPTION AND INTERACTION WITH P107R01CA051497 · NCI · WISTAR INSTITUTE · PI DANG, CHI V. · 1995 to 2025
$5.3MIdentification of Inhibitors of human Lactate Dehydrogenase A (LDHA) as Anti-cancer AgentsZIATR000198 · NCATS · NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES · PI HALL, MATTHEW · 2015 to 2020
$1.2MCCR NIH HHS HHSN261200800001CNCI NIH HHS HHSN261200800001ENCI NIH HHS P30 CA010815NCI NIH HHS R01 CA051497NCI NIH HHS R01 CA057341
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.
Indexed as
AnimalsAntineoplastic AgentsCell Line, TumorCrystallography, X-RayDrug DiscoveryDrug Screening Assays, AntitumorEnzyme InhibitorsHigh-Throughput Screening AssaysHumansL-Lactate DehydrogenaseMaleMembranes, ArtificialMiceMicrosomes, LiverPermeabilityPyrazoles2-(3-((1,1'-biphenyl)-3-yl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acidAntineoplastic AgentsEnzyme InhibitorsL-Lactate DehydrogenaseMembranes, ArtificialPyrazolesThiazoles
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.