Preclinical evaluation of CPL423: a novel potent small-molecule inhibitor of TAM family and FLT3 kinase for cancer therapy

Introduction The TAM family of receptor tyrosine kinases (TYRO3, AXL, MERTK) promotes tumor survival, metastasis, and immune evasion. Its dysregulation across solid and hematologic cancers is associated with therapy resistance and poor outcomes. FLT3 is a key oncogenic driver in acute myeloid leukemia (AML). We report the preclinical characterization of CPL423, a low-molecular-weight inhibitor of all TAMs and FLT3. Method In vitro kinase assays quantified potency and kinome selectivity. Antiproliferative effects were measured in FLT3-ITD-driven AML cell lines (MOLM-13, MV4-11). Antitumor efficacy was evaluated in AML xenografts and A375 melanoma (AXL overexpression, BRAF V600E mutation). Phagocytic capacity of antigen presenting cells was addressed using bone marrow derived dendritic cells (BMDC). Physicochemical, ADME/PK, and cardiovascular safety liabilities were profiled. Result CPL423 inhibited TAMs and FLT3 with sub-nanomolar IC50s (MERTK 0.47 nM; FLT3 0.94 nM) and high selectivity. It suppressed proliferation in MOLM-13 and MV4-11 (IC50 5.7 and 7.92 nM). In AML xenografts, it achieved up to 98% tumor growth inhibition without observable toxicity; in A375, TGI was 39.4% at 50 mg/kg on day 14 Ex vivo experiments showed that the compound altered the clearance of dying cells by dendritic cells (BMDCs), consistent with TAM-pathway modulation. CPL423 showed high permeability, metabolic stability, and low cardiovascular liability. Discussion CPL423 provides direct antitumor activity via dual TAM/FLT3 inhibition and immune-mediated effects on antigen-presenting cells, addressing resistance mechanisms in AML and TAM/AXL-driven solid tumors and supporting further development, including combination regimens.