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Title: Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators

Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Finally, together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [4] ;  [5] ;  [1] ;  [6] ;  [7] ;  [8] ;  [2] ;  [9]
  1. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine, Dept. of Pharmacology
  2. Case Western Reserve Univ., Cleveland, OH (United States). Dept. of Chemistry
  3. Case Western Reserve Univ., Cleveland, OH (United States). Case Comprehensive Cancer Center
  4. Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
  5. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine, Dept. of Biochemistry
  6. Univ. of Deharadun (India).Dehradun Inst. of Technology, Dept. of Chemistry
  7. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine, Dept. of Radiation Oncology
  8. Case Western Reserve Univ., Cleveland, OH (United States). Center for Proteomics and Bioinformatics
  9. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine, Dept. of Pharmacology; Case Western Reserve Univ., Cleveland, OH (United States). Center for Proteomics and the Dept. of Chemistry
Publication Date:
OSTI Identifier:
1236255
Grant/Contract Number:
AC02-06CH11357; R01GM100887; R01CA100827; 5R25CA148052-05; U01 CA062502
Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 24; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES