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Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers
- Source :
- Investigational new drugs. 39(5)
- Publication Year :
- 2021
-
Abstract
- G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.
- Subjects :
- 0301 basic medicine
Male
Cell cycle checkpoint
DNA Repair
DNA damage
Cell Survival
Mice, Nude
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Rats, Sprague-Dawley
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Cell Line, Tumor
Neoplasms
Animals
Humans
Pharmacology (medical)
Pharmacology
BRCA2 Protein
Cell growth
BRCA1 Protein
Xenograft Model Antitumor Assays
Rats
G-Quadruplexes
030104 developmental biology
Oncology
chemistry
Apoptosis
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
PARP inhibitor
Cancer cell
Cancer research
Phthalazines
Homologous recombination
DNA
Subjects
Details
- ISSN :
- 15730646
- Volume :
- 39
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Investigational new drugs
- Accession number :
- edsair.doi.dedup.....371fe7ad0a09e772442504ea1461a377