Discovery of a Series of 5,11-Dihydro-6 H-benzo[ e]pyrimido[5,4- b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors

  • ACS Med Chem Lett. 2016 Aug 2;7(10):908-912. doi: 10.1021/acsmedchemlett.6b00209.
Fleur M Ferguson  1 ,  Jing Ni  1 ,  Tinghu Zhang  1 ,  Bethany Tesar  2 ,  Taebo Sim  3 ,  Nam Doo Kim  4 ,  Xianming Deng  1 ,  Jennifer R Brown  2 ,  Jean J Zhao  1 ,  Nathanael S Gray  1
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
  • 2. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 3. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
  • 4. Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Republic of Korea.
PMID: 27774127 DOI: 10.1021/acsmedchemlett.6b00209
Abstract

Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.

Keywords
PI3K-γ; PI3K-δ; kinase inhibitor; p110-γ; p110-δ; phosphatidylinositol-4,5-bisphosphate 3-kinase-delta.
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