Abstract 3001: Highly selective and oral bioavailable PI3Kγ inhibitor for cancer immunotherapy by targeting myeloid-derived suppressor cells in tumor

Abstract Introduction: Phosphoinositide 3-kinases (PI3Ks) are crucial for cell growth, survival, and metabolism, with dysregulated signaling common in cancer. The PI3K family includes four isoforms—PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ—each with distinct roles, where pan-PI3K inhibition often results in toxicity due to broad isoform expression. Existing various PI3K isoform inhibitors, despite in vitro specificity, often act as pan-inhibitors at high in vivo clinical effective concentrations (1μ M to 5μ M). We developed a highly selective PI3Kγ inhibitor that retains its specificity even at therapeutic in vivo levels, effectively targeting tumor immunosuppressive environment to inhibit tumor growth, while reducing toxicity associated with pan-PI3K inhibitions. Methods: Newly synthesized compounds were screened for PI3K isoform selectivity by kinase binding assays. After oral administration (p.o.), tissue distribution studies compared lead compounds with IPI-549 across various tissues, including tumor, spleen, tumor-draining lymph nodes (TDLNs), plasma and liver. The lead PI3Kγ inhibitors were further evaluated in vivo using MC38 colon cancer model and MMTV-PyMT breast cancer model, in both monotherapy (p.o.) and combination therapy with paclitaxel (PTX) or anti-PD-1 antibody (aPD-1). Immune cell profiling in tumor microenvironment was analyzed by flow cytometry post-treatment. Results: The lead compounds, SH-315 (γ IC50110.4nM, δ IC50>10000nM, β IC50>10000nM, α IC503212nM) and SH-327(γ IC50297.4nM, δ IC50>10000nM, β IC50 >10000nM, α IC502438nM), demonstrated significantly higher selectivity for PI3Kγ compared to IPI-549 (γ IC50 5.5nM, δ IC50 968.8nM, β IC50 1566nM, α IC50 1248nM). Concentrations of SH-315 and SH-327 were higher in target tissues (tumors, spleen, TDLNs), while plasma levels were lower than IPI-549, potentially reducing PI3K inhibitor-related side effects. In MMTV-PyMT model, SH-327 and SH-315 at 20 mg/kg, combined with PTX and aPD-1, led to significantly smaller tumors compared to IPI-549. In MC38 model, SH-315 at 10mg/kg combined with PTX and aPD-1 achieved Complete Response (CR) in 60% mice, where SH-327 at 20mg/kg achieved CR in 75% mice. SH-315 at 10mg/kg decreased CD11b+Ly6C+ myeloid-derived suppressor cells (MDSCs) in MC38 tumor by 24% compared to IPI-549 and increased CD8+ T cells in tumor by 41% than IPI-549, suggesting enhanced immune activation and reduced immunosuppression. Conclusion: The PI3Kγ inhibitors SH-315 and SH-327 demonstrated superior anti-tumor efficacy compared to IPI-549. Treatment with SH-315 and SH-327 reduced immunosuppressive MDSCs and increased cytotoxic CD8+ T cell activity, highlighting their potential to drive anti-tumor responses through targeted immune modulation and supporting their further development for cancer immunotherapy. Citation Format: Hanning Wen, Shuai Mao, Mahamadou Djibo, Chengyi Li, Jinsong Tao, Hongyi Zhao, Qiyan Wang, Weijia Zheng, Bo Wen, Wei Gao, Duxin Sun. Highly selective and oral bioavailable PI3Kγ inhibitor for cancer immunotherapy by targeting myeloid-derived suppressor cells in tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3001.