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

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

Affiliation

  • 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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