2. Academic Validation
  3. Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase

Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase

  • J Med Chem. 2018 Feb 8;61(3):666-680. doi: 10.1021/acs.jmedchem.7b00530.
Sarah E Huff 1,  Faiz Ahmad Mohammed 2,  Mu Yang 1,  Prashansa Agrawal 1,  John Pink 3,  Michael E Harris 4,  Chris G Dealwis 2 5,  Rajesh Viswanathan 6 1
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Arts and Sciences, Case Western Reserve University , Millis Science Center, Room 216, 2074 Adelbert Road, Cleveland, Ohio 44106, United States.
  • 2 Department of Pharmacology, School of Medicine, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, United States.
  • 3 Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, United States.
  • 4 Department of Chemistry, University of Florida , PO Box 117200, Gainseville, Florida 32611, United States.
  • 5 Center for Proteomics and the Department of Chemistry, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, United States.
  • 6 Frank Hovorka Assistant Professor of Chemistry and Scientific Oversight Board Member-Small Molecule Drug Discovery Core, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, United States.
PMID: 29253340 DOI: 10.1021/acs.jmedchem.7b00530
Abstract

Ribonucleotide reductase (RR), an established Cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR reversibly. We herein report the synthesis and biochemical characterization of 25 distinct analogs. We designed each analog through docking to the C-site of hRR based on our 2.7 Å X-ray crystal structure (PDB ID: 5TUS). Broad tolerance to minor structural variations preserving inhibitory potency is observed. E-3f (82% yield) displayed an in vitro IC50 of 5.3 ± 1.8 μM against hRR, making it the most potent in this series. Kinetic assays reveal that E-3a, E-3c, E-3t, and E-3w bind and inhibit hRR through a reversible and competitive mode. Target selectivity toward the R1 subunit of hRR is established, providing a novel way of inhibition of this crucial Enzyme.

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