Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors
| Autor: | Ruoxi Lan, Hui Tian, Dusica Santos, Lizbeth Celeste Deselm, Jing Lin, Donald Bankston, Constantin Neagu, Sherer Brian A, Jennifer Jackson, Jared Head, Jianguo Ma, Xuliang Jiang, Sakeena Syed, Anderson Clark, Andreas Machl, Yufang Xiao, Erik Wilker, Anna Gardberg, Xiaoling Chen, Igor Mochalkin, Bayard R. Huck, Hui Qiu, Christopher Charles Victor Jones, Vikram Dutt, Johnson Theresa L, Andreas Goutopoulos |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.drug_class
Clinical Biochemistry hERG Pharmaceutical Science Carboxamide Antineoplastic Agents Mammary Neoplasms Animal Pharmacology Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Docking (dog) Dogs Drug Discovery Quinazoline medicine Animals Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway chemistry.chemical_classification biology Molecular Structure Chemistry Kinase TOR Serine-Threonine Kinases Organic Chemistry Ribosomal Protein S6 Kinases 70-kDa Haplorhini Rats Molecular Docking Simulation Enzyme Pyrimidines Area Under Curve biology.protein Molecular Medicine Female Proto-Oncogene Proteins c-akt Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry letters. 50 |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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