92P - Discovery of novel AXL and MER inhibitors as potential anticancer and immune modulator drugs

Background

In cancer progression, abnormal expression of AXL could lead to tumor growth and metastasis and resistance to chemotherapy, while MER could identify apoptotic cancer cells and induce immune suppression in the tumor microenvironment. Combination of AXL and MER inhibitors could generate a synergistic effect, enhancing antitumor responses, and further suppressing resistance formed by monotherapy with AXL selective or MER selective inhibitors. According to the explicit function of AXL and MER, the development of dual AXL and MER inhibitors may provide tremendous advantages to cancer patients.

Methods

Based on our experience in the discovery of an anti-EGFR and anti-HER2 clinical candidate, we introduced several AXL-active and MER-active pharmacophores into DBPR112. We also modified the scaffold and the solubilizing groups to improve the drug-like properties. We have constructed a comprehensive SAR study to discover promising AXL and MER inhibitors.

Results

Upon synthesizing about 200 compounds, we identified several potent dual AXL and MER inhibitors. These compounds were evaluated for their anti-AXL and anti-MER activities, as well as their anti-tumor abilities. Our candidate 5K230 exhibited satisfied oral bioavailability (F% = 55%) and promising in vivo antitumor effects in several mouse xenograft models, including MDA-MB-231, 4T1, MC-38 tumors. Our compound also overcome erlotinib-acquired resistance via the combination with erlotinib in the PC9 xenograft model.

Conclusions

We have described the discovery of potential AXL and MER inhibitors, in which we identified potential candidate 5K230 which showed potent anti-AXL and anti-MER activities. Moreover, 5K230 displayed anti-tumor efficacy in several mouse xenograft models. Further preclinical evaluation of 5K230 is underway to develop it as a promising anticancer and immune modulator drug.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

National Health Research Institutes.

Funding

National Health Research Institutes.

Disclosure

All authors have declared no conflicts of interest.