Structure-based drug discovery of novel penta- or hexa-bicyclo-pyrazolone derivatives as potent and selective AXL inhibitors.

AXL is a promising antitumor target due to its important role in tumor growth, poor survival, metastasis, immunosuppression, and drug resistance. Herein, we employed molecular modeling-assisted structural optimization strategies to design and synthesize a series of penta- or hexa-bicyclo-pyrazolone derivatives as novel AXL inhibitors. Compounds with high enzymatic and cellular potencies against AXL are described. Compound w11 showed desirable selectivity for AXL kinase, preferable pharmacokinetic properties, and excellent antitumor efficiency in the MV-4-11 xenograft model. These favorable results demonstrated that compound w11 may serve as a promising therapeutic candidate for hematological malignancy.