Computer-aided identification, synthesis, and biological evaluation of DNA polymerase η inhibitors for the treatment of cancer.
Eur J Med Chem
; 248: 115044, 2023 Feb 15.
Article
in En
| MEDLINE
| ID: mdl-36621139
ABSTRACT
In cancer cells, Pol η allows DNA replication and cell proliferation even in the presence of chemotherapeutic drug-induced damages, like in the case of platinum-containing drugs. Inhibition of Pol η thus represents a promising strategy to overcome drug resistance and preserve the effectiveness of chemotherapeutic drugs. Here, we report the discovery of a novel class of Pol Æ inhibitors, with 35 active close analogs. Compound 21 (ARN24964) stands out as the best inhibitor, with an IC50 value of 14.7 µM against Pol η and a good antiproliferative activity when used in combination with cisplatin - with a synergistic effect in three different cancer cell lines (A375, A549, OVCAR3). Moreover, it is characterized by a favorable drug-like profile in terms of its aqueous kinetic solubility, plasma and metabolic stability. Thus, ARN24964 is a promising compound for further structure-based drug design efforts toward developing drugs to solve or limit the issue of drug resistance to platinum-containing drugs in cancer patients.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ovarian Neoplasms
/
Platinum
Type of study:
Diagnostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2023
Document type:
Article
Affiliation country:
Italia