2. Academic Validation
  3. Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer

Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer

  • Eur J Med Chem. 2024 Jun 17:275:116598. doi: 10.1016/j.ejmech.2024.116598.
Horrick Sharma 1,  Somrita Mondal 2,  Uzziah Urquiza 3,  Colter Esparza 3,  Seth Bartlett 2,  Landon Santa-Pinter 2,  Hanna Hill 3,  Madalyn White 3,  Pragya Sharma 3,  Lerin Luckett-Chastain 4,  Anne Cooper 5,  Mohammad Rasel 5,  Philip Gao 6,  Kevin P Battaile 7,  Surendra K Shukla 8,  Scott Lovell 5,  Michael A Ihnat 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK, USA. Electronic address: horrick.sharma@swosu.edu.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK, USA.
  • 3 Department of Biological & Biomedical Sciences, Southwestern Oklahoma State University, Weatherford, OK, USA.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
  • 5 Protein Structure and X-ray Crystallography Laboratory, The University of Kansas, Lawrence, KS, USA.
  • 6 Protein Production Group, The University of Kansas, Lawrence, KS, USA.
  • 7 New York Structural Biology Center, Upton, NY, USA.
  • 8 Department of Oncology Science, OU College of Medicine, Oklahoma City, USA.
PMID: 38925013 DOI: 10.1016/j.ejmech.2024.116598
Abstract

Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with IC50s of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic Cancer cells. The lead compounds inhibit the proliferation of human pancreatic Cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.

Keywords

Lactate; Lactate Dehydrogenase-A; OXPHOS; Pancreatic cancer; Pharmacokinetics; Small molecule inhibitor.

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