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. Together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.
Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Md Faiz
MF
Ahmad
Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Sarah E
SE
Huff
Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland, Ohio 44106, United States.
John
J
Pink
Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Intekhab
I
Alam
Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Andrew
A
Zhang
Northeastern-CAT at the Advanced Photon Source, Argonne National Laboratory , Argonne, Illinois 60439, United States.
Kay
K
Perry
Department of Biochemistry, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Michael E
ME
Harris
Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Tessianna
T
Misko
Department of Chemistry, Dehradun Institute of Technology, University of Deharadun , Dehradun 248197, India.
Suheel K
SK
Porwal
Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland, Ohio 44106, United States.|Department of Radiation Oncology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Nancy L
NL
Oleinick
Center for Proteomics and Bioinformatics, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Masaru
M
Miyagi
Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Rajesh
R
Viswanathan
Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.|Center for Proteomics and the Department of Chemistry, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Chris Godfrey
CG
Dealwis
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D062126:Databases, Chemical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000970:Antineoplastic Agents; D010797:Phthalimides; D025521:Tumor Suppressor Proteins; D012264:Ribonucleotide Reductases; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase