RÉSUMÉ
Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.
Sujet(s)
Tumeurs , Inhibiteurs de protéines kinases , Protéines proto-oncogènes c-akt , Ribosomal Protein S6 Kinases, 70-kDa , Animaux , Humains , Lignée cellulaire tumorale , Tests de criblage à haut débit , Tumeurs/traitement médicamenteux , Tumeurs/enzymologie , Tumeurs/métabolisme , Phosphatidylinositol 3-kinases/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Protéines proto-oncogènes c-akt/antagonistes et inhibiteurs , Protéines proto-oncogènes c-akt/métabolisme , Ribosomal Protein S6 Kinases, 70-kDa/antagonistes et inhibiteurs , Ribosomal Protein S6 Kinases, 70-kDa/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Stéréoisomérie , Relation structure-activité , Sérine-thréonine kinases TOR/effets des médicaments et des substances chimiquesRÉSUMÉ
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.