Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase γ (PI3Kγ)

  • J Med Chem. 2022 Jan 27;65(2):1418-1444. doi: 10.1021/acs.jmedchem.1c01153.
Guillaume Mata  1 ,  Dillon H Miles  1 ,  Samuel L Drew  1 ,  Jeremy Fournier  1 ,  Kenneth V Lawson  1 ,  Artur K Mailyan  1 ,  Ehesan U Sharif  1 ,  Xuelei Yan  1 ,  Joel W Beatty  1 ,  Jesus Banuelos  1 ,  Jie Chen  1 ,  Elaine Ginn  1 ,  Ada Chen  1 ,  Kimberline Y Gerrick  1 ,  Amber T Pham  1 ,  Kent Wong  1 ,  Divyank Soni  1 ,  Puja Dhanota  1 ,  Stefan G Shaqfeh  1 ,  Cesar Meleza  1 ,  Nell Narasappa  1 ,  Hema Singh  1 ,  Xiaoning Zhao  1 ,  Lixia Jin  1 ,  Ulrike Schindler  1 ,  Matthew J Walters  1 ,  Stephen W Young  1 ,  Nigel P Walker  1 ,  Manmohan Reddy Leleti  1 ,  Jay P Powers  1 ,  Jenna L Jeffrey  1
Affiliations
  • 1. Arcus Biosciences, Inc., 3928 Point Eden Way, Hayward, California 94545, United States.
Abstract

Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production and migration of inflammatory mediators. The inhibition of PI3Kγ has been shown to repolarize the tumor immune microenvironment to a more inflammatory phenotype, thereby controlling immune suppression in Cancer. Herein, we report the structure-based optimization of an early lead series of pyrazolopyrimidine isoindolinones, which culminated in the discovery of highly potent and isoform-selective PI3Kγ inhibitors with favorable drug-like properties. X-ray cocrystal structure analysis, molecular docking studies, and detailed structure-activity relationship investigations resulted in the identification of the optimal amide and isoindolinone substituents to achieve a desirable combination of potency, selectivity, and metabolic stability. Preliminary in vitro studies indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 Macrophages.

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