Definition

An orally bioavailable inhibitor of the receptor tyrosine kinases FMS-like tyrosine kinase 3 (FLT3; CD135; STK1; FLK2), the mast/stem cell factor receptor c-Kit (SCFR; KIT) and colony stimulating factor 1 receptor (CSF1R; CSF-1R; C-FMS; CD115; M-CSFR), with potential antineoplastic and immunomodulating activities Upon administration, FLT3/KIT/CSF1R inhibitor NMS-03592088 binds to and inhibits the activity of FLT3, KIT and CSF1R. This prevents FLT3, KIT and CSF1R-mediated signaling and results in the inhibition of proliferation in tumor cells overexpressing FLT3, KIT and CSF1R. In addition, NMS-03592088 binds to CSF1R expressed on monocytes, macrophages, and osteoclasts and inhibits the binding of the CSF1R ligands colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells. This blocks the production of inflammatory mediators by macrophages and monocytes and reduces inflammation. By blocking the recruitment to the tumor microenvironment and activity of CSF1R-dependent tumor-associated macrophages (TAMs), NMS-03592088 inhibits the immunomodulating activity by macrophages and enhances T-cell infiltration and antitumor T-cell immune responses, which inhibits the proliferation of tumor cells. FLT3, a class III receptor tyrosine kinase (RTK), is overexpressed or mutated in most B lineage neoplasms and in acute myeloid leukemia (AML), and plays a key role in tumor cell proliferation. c-Kit, a transmembrane protein and receptor tyrosine kinase, is overexpressed in solid tumors and hematological malignancies; it plays a key role in the regulation of cell differentiation and proliferation. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor for its ligand colony stimulating factor 1 (CSF1) and plays major roles in tumor cell proliferation and metastasis.