Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors

Abstract

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases

“…On the other hand, from a safety perspective, a high isoform selectivity is required, especially toward PI3Kα and β, which made development of PI3Kγ inhibitors difficult, due to the high similarity between isoform sequences. Only recently, new classes of increasingly more specific inhibitors have been generated to block PI3Kγ kinase activity [ 108 – 110 ]. However, this approach may not discriminate between the two PI3Kγ heteromeric variants, that share the same catalytic p110γ subunit combined to different regulatory subunits, which hypothetically exert distinct biological functions [ 27 ].…”

Development of Azaindole-Based Frameworks as Potential Antiviral Agents and Their Future Perspectives

“…A few phosphoinositide-3-kinase γ(PI3Kγ) inhibitors share common H-bonding donor and acceptor motifs ( Figure 32 ). 122 The bicyclic ring in inhibitors engages in a bidentate manner with Val882, a hinge motif of PI3Kγ. Hence, this bidentate interaction is a determining factor of the potency of different substituted isoindolenones ( Figure 32 ).…”

Unified Approach to Diverse Fused Fragments via Catalytic Dehydrative Cyclization

“…Isoindolinones represent an important class of biologically active small molecules, [4] and have seen increasing use in medicinal chemistry. [5] Of particular interest to our group are tricyclic isoindolinones, which have shown to have antiinflammatory, [6] anti-addictive [7] and CNS modulating effects (Figure 1). [8] Their synthesis often relies upon a linear strategy to build the tricyclic core, which somewhat impedes its use in modular synthesis, with low yielding condensation reactions routinely employed.…”

“…Isoindolinones represent an important class of biologically active small molecules, [4] and have seen increasing use in medicinal chemistry [5] . Of particular interest to our group are tricyclic isoindolinones, which have shown to have anti‐inflammatory, [6] anti‐addictive [7] and CNS modulating effects (Figure 1).…”