Structure-Based Optimization of a Potent, Selective and CNS penetrable p70S6K/AKT Inhibitor M2698 for the Treatment of Tumors with PAM Pathway Genomic Alterations
The PI3K/Akt/mTOR (PAM) pathway is an essential signaling regulator of cell growth, proliferation, and metabolism. Aberrant hyperactivation of the pathway through multiple mechanisms, including loss of tumor suppressor PTEN function, amplification or mutation of Akt and exposure to carcinogens leads to dysregulated cell growth and survival. Clinical evidence suggest that the PAM pathway is an attractive therapeutic target because it serves as a convergence point to cellular processes that contribute to the initiation and maintenance of cancer.
Herein, we present the successful optimization of the quinazoline-8-carboxamide (QCA) series of dual p70S6K/Akt inhibitors. The initial lead MSC2120352 was identified in a focused, kinase library screen. MSC2120352 binds in the ATP-binding pocket of the kinase: the QCA amide group forms bidentate interactions with the hinge region (Glu173-Leu175); the electron-rich π system of the benzyl binds in the G-loop, utilizing noncovalent cation-π interactions with the catalytic lysine-123. Using rational structure-based design, MSC2120352 was subsequently optimized to a highly potent, kinase-selective, CNS penetrant p70S6K/Akt inhibitor M2698.
M2698 delivers a novel mode of PAM pathway inhibition with a different mechanism of action, compared to single-node Akt or p70S6K inhibitors or mTOR rapalogs. In a cellular context, inhibition of p70S6K by M2698 leads to potent inhibition of ribosomal protein S6 phosphorylation, while inhibition of Akt blocks the negative effects of a compensatory feedback loop. In addition, M2698 potently inhibits proliferation of multiple solid tumors, including those with PAM pathway genomic alterations. In vivo pharmacokinetic and efficacy studies of M2698 indicated a dose dependent tumor growth inhibition in models with PAM pathway genomic alterations, including, triple negative breast cancer, Her2+ breast cancer, and glioblastoma. On the basis of its superior in vitro and in vivo profile, M2698 was selected for further development and is currently being evaluated in Phase I clinical studies.