Macrophages (MΦ) not only play a role in host defense and tumor growth, metastasis, and immunosuppression. Many studies have demonstrated that targeting the molecular pathways/signaling nodes in the MΦs that regulate the transition of protumorigenic MΦs into anti-tumorigenic MΦs will activate the immune response in cancer.

Syk kinase has an effect on inflammation and hematopoietic cell responses, including integrin and immunoreceptor tyrosine activation motif (ITAM) signaling. Additionally, the role of Syk is highly controversial, it acts as a tumor promoter or tumor suppressor in different cancers. However, the role of Syk kinase in MΦ-mediated innate immune responses remains unclear. Another target for negative regulation of antitumor immunity is the PI3K signaling pathway, in particular, p110γ in MΦs. Syk kinase and PI3K may activate the antitumor immune response.

With this aim, using computational chemistry methods, the scientists developed a novel chemotype, SRX3207 is an orally active and first-in-class dual Syk/PI3K inhibitor. SRX3207 possesses anti-tumor activity.

In vitro, SRX3207 is able to block p-AKT at 10 μmol/L concentration. In preclinical studies, the scientists used a mouse model with LLC or B16 or B16-OVA or CT26 (1 × 10<sup>5</sup>) cells injected subcutaneously. They treated the mice with SRX3207 by oral gavage with a dose of 10 mg/kg. As a result, the inhibitor blocks phosphorylation of Syk at the 348 sites and Y525/526 site. In addition, SRX3207 blocks immunosuppressive MΦ polarization and blocks tumor growth and increased survival effectively. Thus, SRX3207 possesses efficient anti-tumor activity.

To conclude, SRX3207 potently inhibits Syk and PI3K signaling and augments the antitumor immune response in the lung carcinoma tumor model with no toxicity. In addition, targeting both Syk and p110γ with single-molecule for effective antitumor immunity and to explore SRX3207 in combination with checkpoint inhibitors in cancers.

Shweta Joshi, et al. Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression. Molecular Cancer Therapeutics. 2020.