Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors.
Bioorg Med Chem Lett
; 50: 128352, 2021 10 15.
Article
in En
| MEDLINE
| ID: mdl-34481987
ABSTRACT
Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC50 = 17.4 µM). This agent demonstrated dose-dependent efficacy in inhibiting mice breast cancer tumor growth and covered more than 90% pS6 inhibition up to 24 h at a dose of 200 mg/kg po.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Mammary Neoplasms, Animal
/
Ribosomal Protein S6 Kinases, 70-kDa
/
Proto-Oncogene Proteins c-akt
/
Drug Discovery
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2021
Document type:
Article