Discovery of novel covalent PI3Kδ inhibitors bearing alaninamide moiety by lysine-targeted covalent strategy

PI3Kδ is involved in a wide range of cellular processes, including cell growth, proliferation and differentiation, making it as one of the most valuable targets for the treatment of hematologic tumors. Herein, we developed a series of novel covalent PI3Kδ inhibitors bearing alaninamide moiety by lysine-targeted covalent strategic design. The optimal compound M7, containing the phenolic ester warhead, demonstrated excellent in vitro strong bioactivity and selectivity for PI3Kδ. Furthermore, M7 exhibited potently antiproliferative activity against SU-DHL-6 and Pfeiffer cells. M7 significantly reduced p-AKT levels, arrested the cell cycle and induced cell Apoptosis. Wash-out experiments demonstrated that M7 sustained the inhibitory effect on SU-DHL-6 cells and inhibited p-AKT expression consistently. Protein mass spectrometry confirmed the covalent binding of M7 to K779 of PI3Kδ through amide bonding formation. This study expanded the scope of lysine-targeted covalent design and provided a strong foundation for the development of novel, potent covalent PI3Kδ inhibitors.

Antiproliferation; Lysine-targeted covalent inhibitors; PI3Kδ; Phenolic ester.