Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators
Md Faiz Ahmad1, Sarah E Huff2, John Pink3
1Department of Pharmacology, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
Journal of Medicinal Chemistry
|October 22, 2015
Summary
Researchers discovered novel non-nucleoside small molecules that inhibit Ribonucleotide reductase (RR), a key cancer target. These compounds stabilize the enzyme's inactive form, offering a new therapeutic strategy beyond nucleoside drugs.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Ribonucleotide reductase (RR) is crucial for DNA synthesis and a validated cancer target.
- Current RR inhibitors are primarily nucleoside-based, necessitating exploration of alternative chemical classes.
- Identifying non-nucleoside inhibitors can overcome limitations of existing therapies.
Purpose of the Study:
- To discover novel non-nucleoside small-molecule inhibitors of human Ribonucleotide reductase (RR).
- To characterize the mechanism of action and chemical diversity of these novel inhibitors.
- To evaluate their potential as anti-cancer agents.
Main Methods:
- Virtual screening to identify potential small-molecule inhibitors.
- Biochemical assays to determine binding affinity (KD) and inhibition (IC50).
- Cell toxicity assays to assess anti-cancer potential.
- Kinetic studies and X-ray crystallography to elucidate the mechanism of inhibition.
Main Results:
- Discovery of novel non-nucleoside small molecules targeting RR, including phthalimide derivatives.
- Inhibitors demonstrated micromolar IC50s and KDs, indicating potent activity.
- Crystal structure revealed a noncompetitive inhibition mode by stabilizing inactive RR hexamers.
- Phthalimide compounds were shown to shift the enzyme equilibrium from dimer to hexamer.
Conclusions:
- Several novel non-nucleoside inhibitors of human RR were identified.
- These inhibitors function by stabilizing the inactive hexameric form of the enzyme.
- This discovery offers a new avenue for developing anti-cancer therapeutics targeting RR.
