AXL, a member of the TAM (TYRO3, AXL, and MERTK) subfamily of receptor tyrosine kinases, is overexpressed in a variety of cancer types which has been associated with poor prognosis. In the context of malignancy, evidence suggests that abnormal expression of AXL drives wide-ranging processes, including epithelial to mesenchymal transition, tumor angiogenesis, resistance to chemotherapy as well as targeted therapies, and decreased antitumor immune response. Therefore, AXL is a crucial prognostic biomarker in malignancy and also a promising therapeutic target for antitumor therapies. Herein, we introduce a novel pyrrolopyrimidine derivative DCBCO1601 as potent AXL kinase inhibitor with in vitro and in vivo biological activity. DCBCO1601 significantly inhibited ligand induce AXL signaling pathway activation and potentiated the cytotoxicity of docetaxel in AXL highly expressed H1299 NSCLC cells. The in vitro inhibition activity of DCBCO1601 is superior to the lead AXL inhibitor BGB324, which is currently in phase II clinical trial for treating lung cancer. In addition, combination treatment of DCBCO1601 enhanced the in vivo antitumor activity of docetaxel in H1299 xenograft. DCBCO1601 is being developed as candidate for further clinical development and for IND submission.

Novel pyrrolopyrimidine derivative DCBCO1601 as potent AXL kinase inhibitor with in vitro and in vivo biological activity

2019 Fall National Meeting

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