2. Academic Validation
  3. Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity

Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity

  • Eur J Med Chem. 2020 Dec 15;208:112865. doi: 10.1016/j.ejmech.2020.112865.
Yu Teng 1,  Xinyu Li 2,  Shengnan Ren 1,  Yu Cheng 1,  Kun Xi 3,  Hongtao Shen 1,  Wenzhuo Ma 3,  Guoshun Luo 4,  Hua Xiang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2 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.
  • 3 School of Life and Health Sciences and Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 32987316 DOI: 10.1016/j.ejmech.2020.112865
Abstract

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 (IC50 = 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.

Keywords

B-Cell malignancies; PI3Kδ; Quinazoline derivatives.

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