Growth arrest-specific protein 6 (Gas6) and the tyrosine kinase receptor AXL (Gas6/AXL) signal is one of the major biological paths to mesangial proliferation in kidney. The inhibition of mesangial proliferation via the Gas6/AXL signal is a potential therapeutic target for treating kidney diseases. Seeking to obtain small molecule AXL kinase inhibitors, we conducted screening.  Our screening hit, CH5246453, showed sub-micromolar inhibitory activity to AXL; however, the kinase selectivity was moderate with several drawbacks. Our derivatization of CH5246453 using the structure-activity approach clarified the inhibitory activity and selectivity and erased the drawbacks. As a result, we have obtained our optimized compound, CH5451098, with nano-molar inhibitory activity and high selectivity to AXL. The X-ray co-crystal structure clearly explains the strong AXL inhibitory activity and high selectivity. The compound also displayed a significant efficacy in vivo. We report our efforts which led to CH5451098 and describe its biological activity.

Discovery of selective AXL kinase inhibitor CH5451098 and its biological activity

244th National Meeting (2012)

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