Abstract
PI3Kδ, predominantly expressed in immune cells and markedly dysregulated in B-cell malignancies, emerges as a promising and well-validated therapeutic target in hematologic cancers. Meanwhile, CSF1R regulates the formation and polarization of tumor-associated macrophages (TAMs), facilitating immune suppression and tumor progression in various solid tumors. Although targeting PI3Kδ or CSF1R has shown promise, the clinical application is often constrained by off-target effects, toxicity, and limited efficacy, particularly in solid malignancies. In this study, we identified JMC14, a novel dual inhibitor targeting PI3Kδ and CSF1R with a distinct structure and favorable selectivity among human kinome, yielding IC(50) values of 12 nM against PI3Kδ and 143 nM against CSF1R, respectively. JMC14 preferentially inhibited PI3Kδ-mediated signaling at the cellular level and exhibited robust antiproliferative activity across 10 lines of diffuse large B-cell lymphoma (DLBCL) cells, outperforming the approved PI3Kδ inhibitor idelalisib. Notably, its efficacy negatively correlated with the PI3Kα expression among the cell lines tested, suggesting a compensatory pathway mediated by PI3Kα. Daily oral administration of JMC14 (10, 30, or 100 mg/kg, for 21 days) dose-dependently suppressed tumor progression in xenografts derived from TMD8 cells and DLBCL patients, accompanied by good tolerance. Additionally, M-NFS-60 myeloid leukemia cells, which are dependent on the CSF-1-CSF1R axis for survival and proliferation, were effectively inhibited by JMC14 both in vitro and in vivo, further validating its inhibitory activity targeting CSF1R. Furthermore, JMC14 demonstrated potent antitumor activity in murine triple-negative breast cancer (TNBC), which was associated with its activity to reshape the immune microenvironment by reducing M2-like TAMs, enhancing CD8(+) T cell infiltration. Collectively, these findings establish JMC14 as a potent dual PI3Kδ/CSF1R inhibitor with remarkable efficacy against both hematologic and solid malignancies with hyperactivation of PI3Kδ and/or CSF1R, highlighting the potential of JMC14 as a useful probe to dissect the interaction of PI3Kδ and CSF1R in tumor progression and immune reprogramming.