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

Fleur M Ferguson; Jing Ni; Tinghu Zhang; Bethany Tesar; Taebo Sim; Nam Doo Kim; Xianming Deng; Jennifer R Brown; Jean J Zhao; Nathanael S Gray

doi:10.1021/acsmedchemlett.6b00209

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. eCollection 2016 Oct 13.

Authors

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.

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.