Discovery of AXL Degraders with Improved Potencies in Triple-Negative Breast Cancer (TNBC) Cells

AXL kinase is heavily involved in tumorigenesis, metastasis,
and
drug resistance of many cancers, and several AXL inhibitors are in
clinical investigations. Recent studies demonstrated that the N-terminal distal region of AXL plays more important roles
in cell invasiveness than its C-terminal kinase domain.
Therefore, degradation of AXL may present a novel superior therapeutic
approach than the kinase inhibitor therapy. Herein, we report the
discovery of a series of new AXL PROTAC degraders. One representative
compound 6n potently depletes AXL with a DC50 value of 5 nM in MDA-MB-231 TNBC cells. It also demonstrates significantly
improved potencies against the AXL signaling activation, cell proliferation,
migration and invasion of TNBC cells comparing with the corresponding
kinase inhibitor. Moreover, the compound exhibits promising therapeutic
potential both in patient-derived organoids and a xenograft mouse
model of MDA-MB-231 cells.