Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• The PI3K/Akt/mTOR pathway is frequently activated in human cancers, driving tumor growth.
• Targeting this pathway with dual inhibitors can overcome feedback loops and enhance efficacy.
• Existing quinazoline carboxamide scaffolds provide a basis for developing novel inhibitors.

Purpose of the Study:

• To identify and optimize novel dual inhibitors of p70S6K and Akt.
• To develop a potent and selective drug candidate for cancer therapy.
• To evaluate the in vivo efficacy of the lead compound in a preclinical cancer model.

Main Methods:

• Scaffold docking strategy utilizing a quinazoline carboxamide series.
• Structure-activity relationship (SAR) optimization of identified analogs.
• In vitro enzymatic assays for p70S6K and Akt inhibition.
• In vivo efficacy studies in a mouse breast cancer model.

Main Results:

• Identified 4-aminopyrimidine analog 6 with potent enzymatic activity.
• Optimized analog 37 demonstrated single-digit nanomolar potency against both p70S6K and Akt.
• Compound 37 showed favorable hERG liability and significant dose-dependent inhibition of breast cancer tumor growth in mice.
• Achieved >90% pS6 inhibition up to 24 hours post-administration.

Conclusions:

• A novel dual p70S6K/Akt inhibitor, compound 37, was discovered and optimized.
• This agent shows significant preclinical efficacy in inhibiting cancer progression.
• The developed inhibitor represents a promising therapeutic candidate for targeting the PI3K/Akt/mTOR pathway in cancer.