Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors.
Eur J Med Chem
; 236: 114311, 2022 Jun 05.
Article
in En
| MEDLINE
| ID: mdl-35385803
ABSTRACT
TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 µM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carrier Proteins
/
Adaptor Proteins, Signal Transducing
/
DNA-Binding Proteins
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Eur J Med Chem
Year:
2022
Document type:
Article