Discovery of NTQ2494, a potent and orally bioavailable inhibitor of AXL kinase for the treatment of human tumors.

The receptor tyrosine kinase AXL has emerged as a promising target for overcoming therapeutic resistance in both solid and haematological tumors. Currently, multiple strategies have been established to block AXL activity in tumor cells. Among these, Small-molecule inhibitors exert a more potent inhibitory effect. Although a number of small-molecule compounds have been reported, their ADME profiles and inhibitory efficacy still have considerable potential for further optimization. In this paper, we describe a series of 2,4,5-substituted pyrimidine AXL kinase inhibitors featuring a phosphine oxide moieties that exhibit more powerful inhibitory effect and an improved in vivo pharmacokinetic profiles. Several challenges such as high clearance, hERG risk, CYP450 inhibition, and poor oral pharmacokinetics (PK) were addressed, leading to the identification of NTQ2494 (5p) as the optimal compound. NTQ2494 (5p) exhibited favorable ADMET properties and demonstrated significantly enhanced in vivo efficacy in an MV-4-11 xenograft model compared to TP-0903. NTQ2494 is currently under Phase I clinical evaluation for the treatment of advanced hematological malignancies and solid tumors.