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.

Automated summary

AXL kinase is crucially involved in cancer tumorigenesis, metastasis, and drug resistance, and multiple AXL inhibitors are currently being investigated in clinical trials. Recent research has highlighted the importance of the N-terminal region of AXL in cell invasiveness, suggesting that targeting AXL degradation could be a more effective therapeutic approach compared to kinase inhibitors. In this study, a series of new AXL PROTAC degraders were discovered, with compound 6n emerging as a potent AXL depletor in TNBC cells. It exhibited superior inhibitory effects on AXL signaling activation, cell proliferation, migration, and invasion compared to the corresponding kinase inhibitor. Additionally, compound 6n showed promising therapeutic potential in patient-derived organoids and a mouse model of MDA-MB-231 cells.