title: Structure-based development of small molecule PFKFB3 inhibitors: a framework for potential cancer therapeutic agents targeting the Warburg effect.
abstract: Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts.
authors.affiliation: Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States of America.
authors.forename: Minsuh
authors.initials: M
authors.lastname: Seo
authors.forename: Jeong-Do
authors.initials: JD
authors.lastname: Kim
authors.forename: David
authors.initials: D
authors.lastname: Neau
authors.forename: Inder
authors.initials: I
authors.lastname: Sehgal
authors.forename: Yong-Hwan
authors.initials: YH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005636:Fructosephosphates / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D005636:Fructosephosphates; C027618:fructose-6-phosphate; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2