Sarah E Huff1, Faiz Ahmad Mohammed2, Mu Yang1, Prashansa Agrawal1, John Pink3, Michael E Harris4, Chris G Dealwis2,5, Rajesh Viswanathan6,1. 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.
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.
Ribonucleotide reductase (RR), an established cancer tn class="Chemical">arget, 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.
Authors: Tessianna A Misko; Yi-Ting Liu; Michael E Harris; Nancy L Oleinick; John Pink; Hsueh-Yun Lee; Chris G Dealwis Journal: J Enzyme Inhib Med Chem Date: 2019-12 Impact factor: 5.051