Yu Teng: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Xinyu Li: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China; School of Life and Health Sciences and Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China.
Shengnan Ren: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Yu Cheng: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Kun Xi: School of Life and Health Sciences and Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China.
Hongtao Shen: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Wenzhuo Ma: School of Life and Health Sciences and Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China.
Guoshun Luo: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: gsluo@cpu.edu.cn.
Hua Xiang: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: xianghua@cpu.edu.cn.
Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.
